Interferon-inducible effector mechanisms in cell-autonomous immunity

John D. MacMicking

doi:10.1038/nri3210

Interferon-inducible effector mechanisms in cell-autonomous immunity

MacMicking, John D. 2012-04-25 00:00:00 REVIEWS Interferon-inducible effector mechanisms in cell-autonomous immunity John D. MacMicking Abstract | Interferons (IFNs) induce the expression of hundreds of genes as part of an elaborate antimicrobial programme designed to combat infection in all nucleated cells — a process termed cell-autonomous immunity. As described in this Review, recent genomic and subgenomic analyses have begun to assign functional properties to novel IFN-inducible effector proteins that restrict bacteria, protozoa and viruses in different subcellular compartments and at different stages of the pathogen life cycle. Several newly described host defence factors also participate in canonical oxidative and autophagic pathways by spatially coordinating their activities to enhance microbial killing. Together, these IFN-induced effector networks help to confer vertebrate host resistance to a vast and complex microbial world. Host effector mechanisms are essential for the survival examination of newly described ISGs reveals a highly Autophagy of all multicellular organisms. This is exemplified by di verse but integrated host defence programme dedicated A specialized process involving 13–16 cell-autonomous immunity in plants, worms, flies and to protecting the interior of a vertebrate cell . the degradative delivery of a portion of the cytoplasm or of mammals. In Arabidopsis spp., for example, a defin- When viewed on a microscopic scale, the cell int-e damaged organelles to the able set of resistance genes is mobilized during this rior represents an immense ‘subterranean landscape’ lysosome. Internalized programmed cell-intrinsic response to protect against to patrol and defend. A single human macrophage, for pathogens can also be diverse phytopathogens; this inherited response is example, occupies ~5,000 μm (REF. 17). Contrast this with eliminated by this pathway. 1,2 3 sometimes referred to as the ‘resistome’ . In higher spe- a mature HIV-1 particle (~200 nm ) or tubercle bacillus cies, however, the assembly of an antimicrobial arsenal (~5–10 μm ) and it quickly becomes apparent that most or resistome takes on multiple forms, because the bur - IFN-induced proteins will need to be dispatched to the 18,19 den posed by infection in these organisms is consider- site of pathogen replication to be effective . Likewise, able . Indeed, as many as 1,400 phylogenetically distinct the ability of compartmentalized pathogens to remain microorganisms can infect a single chordate host . largely sequestered in vesicles suggests that many IFN- To cope with this increased microbial challenge, vert-e induced effectors also need methods to detect these brates have evolved additional levels of cell-autonomousm embrane-bound sanctuaries to eliminate the resident 18–20 control beyond the pre-existing repertoire of constitutive pathogens . host defence factors. These additional factors include Several ISGs fulfil both criteria. Members of an emer- g hundreds of gene products that are transcribed in ing superfamily of GTPases with immune functions recog - response to signals originating from the interferon (IFN), nize specific host lipid molecules on the pathogen vacuole 21–23 tumour necrosis factor (TNF), interleukin-1 (IL-1) and to mark it for disruption or delivery to lysosomes . 5,6 Toll-like receptor (TLR) families. Many of the induced Other recently identified IFN-induced proteins detect Section of Microbial proteins confer direct microbicidal immunity in al l ubiquitylated bacteria in the cytosol or exposed glycans Pathogenesis, Boyer Centre 7–9 25 nucleated cells . on host membranes that have been damaged by bacteria , for Molecular Medicine, IFNs are among the most potent vertebrate-derived and these markers stimulate the removal of the infecting 295 Congress Avenue, Yale University School of signals for mobilizing antimicrobial effector functions organism through autophagy. In addition, new antiviral Medicine, New Haven, 8,10,11 against intracellular pathogens . Nearly 2,000 human factors distinguish the cell ular entry, replication and exit Connecticut 06510, USA. 13,15 and mouse IFN-stimulated genes (ISGs) have been iden- points of HIV-1 and influenza A viruses . Less dis- e‑mail: tified to date, most of which remain uncharacterized (see criminating effector mechanisms are also deployed; for [email protected] 12 – doi:10.1038/nri3210 the Interferome database) (FIG. 1). The recent large-scale example, diatomic radical gases such as superoxide (O ) NATUR E R EVIEWS | IMMUNOLOGY VOLUME 12 | MAY 2012 | 367 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS and nitric oxide (NO) circumvent the need for recogni- a property first noted for NO against herpes simplex tion of the membranes surrounding sequestered bacte- virus, ectromelia virus and vaccinia virus . Both of these 7,26 ria and protozoa inside host cells . Because such gases strategies rely on an expanded family of oxidoreductases can diffuse large distances (several micrometres), they can and peroxidases that is now known to be present in also enter adjacent cells to confet r rans-acting immunity, essentially all phyl.a Arabidopsis Caenorhabditis Strongylocentrotus Drosophila Danio rerio Mus Homo sapiens thaliana elegans purpuratus melanogaster musculus sapiens Constitutive and inducible cell-autonomous defence IFN-inducible eﬀectors Type I Type III Type II IFN IFN IFN IFNGR1 IFNGR2 IFNAR1 IFNAR2 IL-10R2 IFNLR1 Cytoplasm JAK2 JAK2 TYK2 JAK1 TYK2 JAK1 P P P P GAF P P ISGF3 IRF9 Nucleus Type II IFN eﬀectors: Type I and type III IFN eﬀectors: DUOXs, NOXs, P ADAR, NOS2, Galectins, NRAMP1, APOBECs, PKR, GBPs, SQSTM1, GBPs, OASs, IDO, PKR, IRF9 IFITMs, SAMHD1, IFITMs, Tetherin, IRGs, Tetherin, IRGs, TRIMs, GAS ISRE ISG15, TRIMs, NDP52, Viperin NOS2, MXs, Viperin Antibacterial, antiprotozoal and Antiviral and antibacterial antiviral host defence programmes host defence programmes Figure 1 | Evolution of IFN-induced cell-autonomous host defence. a | The evolution of cell-autonomous immunity Nature Reviews | Immunology and the emergence of interferon (IFN)-induced effector mechanisms around the protochordate – vertebrate split (~530 million years ago). b | Cell-autonomous host defence proteins are canonically induced by IFNs via three receptor complexes −1 8 with high affinities for their ligands (K < 10 nM ) . The first receptor complex is a tetramer — composed of two chains of IFNγ receptor 1 (IFNGR1) and two chains of IFNGR2 — that engages type II IFN (that is, IFN γ) dimers. The second is a heterodimer of IFNα/β receptor 1 (IFNAR1) and IFNAR2 that binds to the type I IFNs: a family consisting of 13 different IFN α subtypes and one IFNβ subtype in humans. In the third receptor complex, interleukin-10 receptor 2 (IL-10R2) associates with IFNλ receptor 1 (IFNLR1; also known as IL-28Rα) to bind to three different type III IFN (that is, IFNλ) ligands (see REF. 8). Following receptor–ligand engagement, signals are transduced through signal transducer and activator of transcription 1 (STAT1) homodimers in response to IFNγ or through STAT1–STAT2 heterodimers in response to type I IFNs or IFN λ. Following their recruitment to the receptor complexes, these STAT molecules are phosphorylated by receptor-bound tyrosine kinases (namely, Janus kinases (JAKs) and tyrosine kinase 2 (TYK2)). Phosphorylated STAT1 homodimers (also known as GAF) translocate to the nucleus to bind to IFNγ-activated site (GAS) promoter elements to promote the IFN-induced expression of antimicrobial effector genes, some of which also require transactivation by IFN-regulatory factor 1 (IRF1) and IRF8. In the case of type I and III IFN signalling, phosphorylated STAT1–STAT2 dimers form a complex with IRF9 to yield IFN-stimulated gene factor 3 (ISGF3); this complex also translocates to the nucleus, where it binds to IFN-stimulated response elements (ISREs) in the promoters of different or overlapping IFN-stimulated effector genes. 368 | MAY 2012 | VOLUME 12 w w w.nature.com/reviews/immunol © 2012 Macmillan Publishers Limited. All rights reserved STAT1 STAT1 STAT1 JAK1 JAK1 STAT1 STAT1 STAT1 STAT1 STAT1 STAT2 STAT2 STAT2 REVIEWS It is the purpose of this Review to provide a broad bacteria . In mammals, three classes of cytokine- conceptual framework for understanding IFN-induced inducible oxidoreductases control ROS and RNS pro - cell-autonomous host defence and to highlight the grow - duction. NADPH oxidases (NOXs) directly catalyse the ing list of effectors that combat internalized bacteria, production of O , whereas dual oxidases (DUOXs) protozoa and viruses at the level of the infected mamma - produce H O (TABLE 1; Supplementary information 2 2 Reactive oxygen species lian cell. It focuses principally on the downstream killingS1 (figure)). In addition, nitric oxide synthases (NOSs) (ROS). Aerobic organisms derive their energy from the mechanisms, rather than on the well-known upstream synthesize NO, and the immunologically inducible reduction of oxygen. The microbial recognition and signalling events that elicit isoform NOS2 (also known as iNOS) synthesizes large metabolism of oxygen, and in IFN production. amounts of NO under infectious conditions. All three particular its reduction through classes of oxidoreductases may act simultaneously, the mitochondrial Cell-autonomous defence against bacteria sometimes even within the same host cell, depending electron-transport chain, generates by-products such as Bacteria infect host cells either through active inva - on the physiological setting and the activating stim - superoxide (O ) and 7,28 sion or via engulfment by professional phagocytes. uli . Non-enzymatic sources of ROS and RNS can downstream intermediates such Following their uptake, some bacterial species — such also contribute to host defence. For example, O can as hydrogen peroxide (H O ) 2 2 · as Mycobacterium tuberculosis and Salmonella enterica originate from mitochondrial leakage and NO can be and hydroxyl radicals ( OH). These three species are referred serovars — inhabit membrane-bound compartments generated by the action of gastric acid on NO that to as ROS. ROS can damage termed phagosomes, which they modify to limit is produced from dietary nitrates (NO ) by the oral important intracellular targets, 20 7,28,31,32 their exposure to microbicidal factors . By contrast, microbiota . such as DNA, lipids or proteins. Chlamydia spp. reside in reticulate structures called The NOX family of enzymes (NOX1 to NOX5) are inclusion bodies, which intercept Golgi-derived exo - the major ROS producers during infection . NOX2 Reactive nitrogen species (RNS). Nitric oxide (NO) cytic traffic as a source of nutrition . Other bacterial (also known as phagocyte oxidase) is responsible for the chemistry is complex because species, including Listeria and Shigella spp., escape respiratory burst in neutrophils, monocytes, macrophages of the extreme reactivity of their vacuoles to replicate in the cytosol. In each su- b and eosinophils. Genetic evidence underscores its impor - NO, which can result in the cellular locale, IFN-induced effector mechanisms are tance for host defence; indeed, congenital mutations in formation of different reactive nitrogen intermediates (RNI) mobilized to defend the interior of the host cell against genes encoding NOX2 subunits give rise to a collec - depending on the amount of bacterial infection. These mechanisms rely on oxida - tive syndrome termed chronic granulomatous disease. NO that is produced by cells. tive, nitrosative and protonative chemistries, as well Affected individuals suffer from recurrent infections with At low concentrations, NO as nutriprive (nutrient-restrictive) and membranolytic catalase-positive organisms such as Staphylococcus aureus, reacts directly with metals and activities. Serratia marcescens, Burkholderia cepacia, non-typhoidal other radicals. At higher 28,33 concentrations, indirect effects Salmonella spp. and M. tuberculosis (TABLE 2). prevail, and these include IFN-induced oxidative and nitrosative defence. NOX2 is a multisubunit enzyme comprising a trans- several oxidation or Cytotoxic gases are one of the most ancient and impor- membrane heterodimer — composed of gp91phox (also nitrosylation reactions with tant forms of cell-autonomous defence. These gases known as CYBB) and p22phox (also known as CYBA) oxygen that result in the production of various — collectively termed reactiv e oxygen species (ROS) — and three cytosolic subunits, namely p67phox (also congeners. NO and related RNI and reactive nitrogen species (RNS) — are generated by known as NCF2), p47phox (also known as NCF1) and are effective antimicrobial oxido reductases to confer microbicidal activity and p40phox (also known as NCF4). The cytosolic subunits agents and signal-transducing 7,26,28,30 regulate intracellular signalling . The targets of have SH3 domains that mediate intersubunit contacts molecules. ROS and RNS include bacterial DNA (which is dam - and PX domains for binding membrane lipids once Phagolysosomes aged via guanine base oxidation), lipids (which are they translocate to the gp91phox–p22phox complexes Intracellular vesicles that result damaged via peroxidation), and haem groups or iron– at the plasma membrane or on plasma membrane- from the fusion of phagosomes, 7,26 28 sulphur clusters within bacterial enzymes . Much of derived phagosomes (TABLE 1; Supplementary infor- which enclose extracellular the redox damage caused by these gases can be traced mation S1 (figure)). The assembly and activation of material that has been ingested, with lysosomes, to derivatives of O and NO. For example, the sequen- NOX2 holoenzymes also requires several GTPases. which contain lytic enzymes tial addition of single electrons to O yields hydrogen RAC1 and RAC2 facilitate this process under basal and antimicrobial peptides. peroxide (H O ) and then the hydroxyl radical (OH), conditions , whereas the recently described GTPase 2 2 both of which are more powerful oxidants than their guanylate-binding protein 7 (GBP7) operates after NADPH oxidases 26 – 16 pre decessor . Likewise, the reaction of NO with O , IFNγ stimulation . IFNγ-induced GBP7 specifi- Enzyme systems that consist of multiple cytosolic and other ROS or thiols yields intermediates with potent cally recruits cytosolic p67phox–p47phox heter-o membrane-bound subunits. bactericidal properties: dinitrogen oxides (N O and dimers to gp91phox–p22phox complexes on bacterial 2 3 The complex is assembled in N O ), compound peroxides (ONOO ) and nitroso- phagosomes containing Listeria monocytogenes or 2 4 activated phagocytic cells on 7,26 16 thiol adducts (RSNO) . Within phagolysosomes, Mycobacterium bovis bacillus Calmette–Guérin (BCG) the plasma and phagosomal membranes. NADPH oxidase O undergoes spontaneous dismutation to H O , and (FIG. 2). The proximity of phagosomal NOX2 to intra- 2 2 2 uses electrons from NADPH to stable nitrogenous end products such as nitrite (NO ) luminal bacteria may heighten IFN-induced killing, as reduce molecular oxygen to are converted back at low pH to the volatile NO gas; subsequent fusion with lysosomes favours dismutation form superoxide anions. 7,9 – both mechanisms aid bacterial killing . of O to the more-damaging oxidant H O (REF. 9). In Superoxide anions are 2 2 2 Given the toxicity of these molecules, it is not sur - addition to GBP7, the IFNγ-activated GTPase leucine- enzymatically converted to hydrogen peroxide, which in prising that the production of ROS and RNS is tightly rich repeat kinase 2 (LRRK2) has recently been reported neutrophils can undergo 34 controlled and often compartmentalized to limit to promote NOX2 activity against S. Typhimurium . further conversion by self-injury. This has the added benefit of maximiz- How LRRK2 exerts its effects and whether it works myeloperoxidase to ing microbicidal activity when production is loca-l in tandem with GBP7 on phagosomal membranes is hypochloric acid, a highly toxic and microbicidal agent. ized to phagosomes and phagolysosomes that contain currently unknown. NATUR E R EVIEWS | IMMUNOLOGY VOLUME 12 | MAY 2012 | 369 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS Other IFNγ-induced enzymes provide oxidative such mechanisms operate during vertebrate immu- Respiratory burst defence in non-phagocytic cells, such as epithelial cells nity in vivo . Thus, IFN-inducible NOXs and DUOXs The process by which molecular oxygen is reduced lining the airways, oral cavity and gastrointestinal tract. restrict bacterial colonization not only of immune cells by the NADPH oxidase system The IFNγ-inducible enzymes NOX1 and DUOX2 but also of stromal cells. to produce reactive oxygen – 28 generate O and H O , respectively, in these cells NOS2 is expressed in a variety of immune and non- 2 2 2 species. (Supplementary information S1 (figure)). At the plasma immune cell types following stimulation by type I IFNs membrane, H O can form hypothiocyanite (OSCN ), (that is, IFNα and IFNβ) and by IFNγ. Signals from Chronic granulomatous 2 2 disease which acts as a potent chemorepellent against bacte - otTM her cytokines (notably, TNF, lymphotoxin-α and TM An inherited disorder caused 35–37 HB HB FAD NADPH rial invasion and killL s isteria and Salmonella spp. . IL-1β) anHB d from microbHB ial proFA duDcts NADPH (such as lipopol-y TM TM by defective oxidase activity in Indeed, recent reports show that impaired clearance of saccharides and lipopeptides) also synergize with IFNs HB HB FAD NADPH HB HB FAD NADPH the respiratory burst of 7,39 Salmonella spp. follows the silencing of DUOX expre -s for NOS2 induction . To date, most work has focused phagocytes. It results from PX PR SH3 PB1 SH3 PX PR SH3 PB1 SH3 mutations in any of five genes sion in zebrafish intestinal epithelium, indicating that on NOS2 activities in mouse macrophages, as human TM that are necessary to generate PX SH3 SH3 AIR PR PX PX PR PR SH3 SH3 PB1 PB1 SH3 SH3 PX SH3 SH3 AIR PR HB HB FAD NADPH the superoxide radicals TM TM TM TM TM PX PX SH3 SH3 SH3 PC AIR PR PX SH3 SH3 AIR PR required for normal phagocyte TM PX SH3 PC HB HB FAD NADPH HB HB FAD NADPH HB HB HB HB FA FAD D NADPH NADPH HB HB FAD NADPH function. Affected patients HB HB FAD NADPH Table 1 | IFN-induced effector molecules that combat intr TMacellular bacteria and parasites PX PX SH3 SH3 PC PC PX PR PB1 SH3 PX PX PR PRSH3 PB1PB1 SH3SH3 suffer from increased HB HB FAD NADPH IFN-induced effector Member or subunit Domain structure susceptibility to recurrent PX PX SH3 PR SH3 PB1 PRSH3 TM TM TM PX PX SH3 PR SH3 PB1 AIRSH3 PR PX SH3 SH3 PR PX PX PR PR SH3 SH3 PB1 PB1 SH3 SH3 PX PX PR PR SH3 SH3 PB1 PB1 SH3 SH3 PX PR SH3 PB1 SH3 infections. TM PX PR SH3 PB1 SH3 NOX family gp91phox HB HB HB HB HB HB FA FA FAD D D NADPH NADPH NADPH TM TM TM TM TM TM PX SH3 SH3 PR PX HB SH3 SH3 HB PR FAD NADPH PX SH3 PC PX PX PX PRSH3 SH3SH3 SH3 SH3 PB1 AIR AIR PR PRSH3 PX SH3 SH3 AIR PR PX PX HB SH3 SH3 SH3 SH3 HB AIR AIR FAD PR PR NADPH HB HB HB HB FA FAD D NADPH NADPH HB HB HB HB HB HB FA FA FAD D D NADPH NADPH NADPH PX SH3 SH3 AIR PR PerD EF HB HB FAD NADPH PerD EF HB HB FAD NADPH PX PR PB1 SH3 p22phox PX PX PX SH3 SH3 SH3 SH3 PC PC AIR PR PX PX SH3 SH3 PC PC PX SH3 PC PX PX PRSH3SH3 PCPB1 SH3 PX PX PR PR SH3 SH3 PB1 PB1 SH3 SH3 PerD EF HB HB FAD NADPH PPerD erD PX EF EF PR SH3HB HB PB1 HB HBSH3 FA FAD D NADPH NADPH PerD EF HB HB FAD NADPH PX PX PX PRSH3 SH3 SH3 SH3 PCPB1PR SH3 p67phox PX PX PR PR PB1 PB1 SH3 SH3 PX PX PX PX PX PR PR PR PR PRSH3 SH3 SH3 SH3 PB1PB1 PB1 PB1 PB1 SH3SH3 SH3 SH3 SH3 PX PX PR PRSH3 PB1PB1 SH3SH3 PX PR PB1 SH3 PX SH3 SH3 AIR PR PX PX SH3 SH3 SH3 SH3 AIR AIR PR PR PX PR PB1 SH3 PerD EF HB HB FAD NADPH PerD PX EF SH3 HBSH3 AIR HB PR FAD NADPH PX SH3 SH3 AIR PR PX SH3 SH3 PR p47phox PX PX PX PX PX SH3 SH3 SH3 SH3 PR SH3 SH3 SH3 SH3 PB1 AIR AIR AIR PRSH3 PR PR PR PX PX PX PX SH3 SH3 SH3 SH3 SH3 SH3 SH3 SH3 AIR AIR PR PR PR PR PX SH3 SH3 PR PX SH3 PC PX PX PX SH3 SH3 SH3 SH3 PC PC PR PX SH3 PC PerD EF HB HB FAD NADPH PX SH3 PC PX SH3 SH3 PR p40phox PX PX PX PX SH3 SH3 SH3 SH3 PC PC PC PC PX SH3 PC PX PX PX PR PR PR PB1 PB1 PB1 SH3 SH3 SH3 PerD PX EF PR HB PB1 SH3 HB FAD NADPH PPerD erD EF EF HB HB HB HB FA FAD D NADPH NADPH PerD EF HB HB FAD NADPH PerD EF HB HB FAD NADPH PerD PX EF PR HB PB1 SH3 HB FAD NADPH NOXA1 HB PX PXBH CaM PR PR FMN/F PB1 PB1 ADSH3 SH3 NADPH HB PX PX PXBH CaM PR PR PR FMN/F PB1 PB1 PB1 ADSH3 SH3 SH3 NADPH PerD EF4 HB HB FAD NADPH PX PX SH3 SH3 SH3 SH3 PR PR PX SH3 SH3 PR PX SH3 SH3 PR PPPerD erD erD EF EF EF HB HB HB HB HB HB FA FA FAD D D NADPH NADPH NADPH PerD EF HB HB FAD NADPH PerD PX EF SH3 HBSH3 PR HB FAD NADPH PerD HB PXBH EF SH3 CaM HBSH3 FMN/FAD PR HB NADPH FAD NADPH NOXO1 HB PX PX PX PXBH SH3 SH3 SH3 SH3 CaM SH3 SH3 SH3 SH3 FMN/FAD PR PR PR PR NADPH PerD EF4 HB HB FAD NADPH PerD EF HB HB FAD NADPH GD DUOX family DUOX1 PPPerD erD erD GDEF EF EF HB HB HB HB HB HB FA FA FAD D D NADPH NADPH NADPH PerD EF HB HB FAD NADPH PerD EF HB HB FAD NADPH PPerD erD EF EF HB HB HB HB FA FAD D NADPH NADPH PPPerD erD erD GDEF EF EF CTHD HB HB HB HB HB HB FA FA FAD D D NADPH NADPH NADPH GD GD GD CTHD DUOX2 HB BH CaM FMN/FAD NADPH PPPerD erD erD EF EF EF HB HB HB HB HB HB FA FA FAD D D NADPH NADPH NADPH PerD EF HB HB FAD NADPH PerD EF HB HB FAD NADPH M GD CTHD PPerD erD EF EF HB HB HB HB FA FAD D NADPH NADPH M PPPerD erD erD GD GD GDEF EF EF CTHD CTHD CTHD HB HB HB HB HB HB FA FA FAD D D NADPH NADPH NADPH DUOXA1 or DUOXA2 HB HB BH BH CaM CaM FMN/F FMN/FAD AD NADPH NADPH HB BH CaM FMN/FAD NADPH HB BH44 CaM FMN/FAD NADPH HB BH4 CaM FMN/FAD NADPH HB BH CaM FMN/FAD NADPH M GD CTHD M GD CTHD GD NOS family NOS2 HB BH CaM FMN/FAD NADPH GD CTHD P GD CTHD P GD CTHD IRG family Human IRGM (a to e isoforms)* GD GD GD GD GD HB HB HB GDBH BH BH CaM CaM CaM ∆CTHDFMN/F FMN/F FMN/FAD AD AD NADPH NADPH NADPH GD GD CTHD P GD GD 444 ∆CTHD CTHD P M HB GDBH CaMCTHD FMN/FAD NADPH HB GD GDBH CaMCTHD CTHD FMN/FAD NADPH Mouse IRGM1 to IRGM3 GD GD CTHD CTHD HB HB GD GDBH BH4 CaM CaMCTHD FMN/F FMN/FAD AD NADPH NADPH HB HB HB BH BH BH CaM CaM CaM FMN/F FMN/F FMN/FAD AD AD NADPH NADPH NADPH GD 444 CTHD GD ∆CTHD GD ∆CTHD TM TM M GD CTHD M GD CTHD M M GD GD GD CTHD CTHD CTHD IRGA, IRGB, IRGC or IRGD M GD CTHD M GD CTHD GD GD GD groups GD CTHD P TM TM M GD GD CTHD GD GD GD GD GD GD GD CTHD GD GD CTHD CTHD GBP family Human GBP1 to GBP6 and GD ∆CTHD GD GD GD CTHD CTHD CTHD PP GD CTHD P GD CTHD P GD CTHD P GD CTHD mouse GBP1 to GBP11 GD GD GD GD GD CTHD CTHD CTHD CTHD CTHD P GD CTHD M M M GD GD GD CTHD CTHD CTHD OR HB OR HB M GD GD ∆CTHD CTHD GD ∆CTHD GD GD GD ∆CTHD ∆CTHD CTHD P TM GD ∆CTHD M GD CTHD M M GD GD CTHD CTHD M M M GD GD GD GD ∆CTHD CTHD CTHD CTHD Human GBP3ΔC OR OR HB HB GD ∆CTHD TM TM TM TM NRAMP family NRAMP1 TM GD GD GD CTHD CTHD CTHD PPP TM GD CTHD P CRD1 CRD2 CRD1 GD CRD2 CTHD P GD GD GD CTHD CTHD CTHD PPP TM GD GD CTHD CTHD PP GD GD GD ∆CTHD ∆CTHD ∆CTHD GD ∆CTHD IDO family IDO1 or IDO2 CRD1 CRD2 OR HB NLDCRD1 CRD2 CRD2 GD ∆CTHD NLD GD GD ∆CTHD ∆CTHD CRD2 GD GD GD ∆CTHD ∆CTHD ∆CTHD TM TM TM Galectin family Galectin 3 NLD CRD2 TM NLDCRD1 CRD2 CRD2 OR OR HB HB OR HB CRD1 CRD2 OR OR HB HB TM TM TM TM TM OR HB TM Galectin 8 or galectin 9 CRD1 CRD2 CRD1 CRD2 OR HB CRD1 CRD2 LIR LIR Ubiquitin-binding SQSTM1 NLDCRD1 CRD2 CRD2 CRD1 CRD1 CRD2 CRD2 CRD1 CRD2 PB1 CRD1ZZ CRD2 OR UBA HB ‡ OR OR HB HB PB1 ZZ UBA CRD1 CRD2 receptors LIR LIROR HB OR HB OR OR OR HB HB HB NLDCRD1 CRD1 CRD2 CRD2 CRD2 OR OR HB HB NLD CRD2 NLD NLD CRD2 CRD2 LIZ NLD PB1 PB1 ZZ ZZ CRD2UBA UBA NDP52 LIZ NLD CRD2 CC UBA CC UBA NLDCRD1 CRD2 CRD2 CRD1 CRD2 CRD1 CRD1 CRD2 CRD2 LIZ LIZ CRD1 CRD2 CRD1 CRD1 CRD1 CRD2 CRD2 CRD2 CRD1 CRD2 AIR, autoinhibitory region; BH, tetrahydrobiopterin-binding domain; CaM, calmodulin-binding domain; CC, coiled-coil; CTHD, CRD1 CRD2 LIR CC UBA CC UBA CRD1 CRD2 CRD1 CRD1 CRD1 CRD2 CRD2 CRD2 CRD1 CRD1 CRD1 CRD2 CRD2 CRD2 C-terminal helical domain; CRD, carbohydrate-recognition domain; DUOX, dual oxidase; EF, EF hand domain; FAD, flavin adenine PB1 ZZ UBA NLD NLD NLD CRD2 CRD2 CRD2 Nature Reviews Nature Reviews dinucleotide binding site; FMN/FAD, flavin mononucleotide or flavin adenine dinucleotide binding site; GBP, guanylate-binding NLD CRD2 LIR LIR LIR LIR LIR NLD CRD2 NLD CRD2 NLD NLD NLD NLD CRD2 CRD2 CRD2 CRD2 LIR protein; GD, GTPase domain; HB, haem-binding site; IDO, indoleamine 2,3 -dioxygenase; IFN, interferon; IRG, immunity-related LIZ PB1 PB1 CRD1 CRD1 CRD1ZZ ZZ CRD2 CRD2 CRD2UBA UBA PB1 ZZ UBA PB1 PB1 ZZ ZZ UBA UBA Natur Nature Re e Reviews views GTPase; LIR, LC3-interacting region; LIZ, LC3-interacting zipper; M, myristoylation site; NADPH, nicotinamide adenine PB1 CRD1ZZ CRD2 LIR UBA CC UBA CRD1 CRD2 CRD1 CRD2 CRD1 CRD1 CRD1 CRD1 CRD2 CRD2 CRD2 CRD2 dinucleotide phosphate binding site; NLD, non-lectin domain; NOS, nitric oxide synthase; NOX, NADPH oxidase; NRAMP, natural LIZ LIZPB1 ZZ UBA LIZ LIZ LIZ resistance-associated macrophage protein; OR, oxidoreductase domain; P, isoprenylation site; PB1, phox and Bem1 domain, LIZ CC CC UBA UBA CC UBA CC CC LIR UBA UBA LIR LIR PC, phox and Cdc domain; PerD, peroxidase domain; PR, proline-rich domain; PX, phox domain for phospholipid binding; CC UBA LIZ LIR Nature Reviews PB1 ZZ UBA RR, arginine-rich domain; SH3, SRC homology 3 domain; SQSTM1, sequestosome PB1 PB1 ZZ ZZ1; TM, transmembr LIR UBA UBA ane domain; UBA, ubiquitin- LIR LIR LIR LIR LIR CC UBA PB1 ZZ UBA associated domain; ZZ, zinc fingers. *Human IRGM is constitutively expressed but participates in IFN-induced cell-autonomous PB1 ZZ UBA PB1 PB1 PB1 ZZ ZZ ZZ UBA UBA UBA PB1 PB1 ZZ ZZ UBA UBA LIZ Natur Nature Re e Reviews views immunity. Denotes indirect effectors that function via autophagy (only LIZ LIZIFN-inducible receptors are shown). Nature Reviews Natur Nature Re e Reviews views Nature Reviews LIZ CC UBA LIZ CC CC UBA UBA LIZ LIZ LIZ LIZ LIZ CC UBA Nature Reviews CC UBA CC CC CC UBA UBA UBA CC CC UBA UBA 370 | MAY 2012 | VOLUME 12 w w w.nature.com/reviews/immunol Nature Reviews Natur Nature Re e Reviews views Nature Reviews Nature Reviews © 2012 Macmillan Publishers Limited. All rights reserved Natur Natur Nature Re e Re e Reviews views views Natur Nature Re e Reviews views REVIEWS Table 2 | Genetic deficiencies in IFN-induced effector genes and susceptibility to infection Host locus Deficiency Susceptibility to intracellular pathogens Refs Human CYBA (encoding Autosomal mutation; B. cepacia, G. bethesdensis, M. tuberculosis, S. aureus, 28,33 p22phox)* complete or partial S. marcescens, Salmonella spp. CYBB (encoding X-linked mutation; gp91phox)* complete or partial IRGM Autosomal mutation; AIEC, M. tuberculosis 66–69 polymorphic MX1 Autosomal mutation; HBV57, HCV, measles virus 128 polymorphic NOS2 Autosomal mutation; M. tuberculosis 164 polymorphic SLC11A1 (encoding Autosomal mutation; M. tuberculosis 83 NRAMP1) polymorphic Mouse Cybb (encoding X-linked mutation; A. baumannii, A. phagocytophila, G. bethesdensis, 28,40,41 gp91phox) complete H. pylori, L. monocytogenes, S. aureus, S. Typhimurium Gbp1 Autosomal mutation; L. monocytogenes, M. bovis BCG, S. Typhimurium 16 complete Gbp5 Autosomal mutation; L. monocytogenes complete Ifitm3 Autosomal mutation; Influenza A virus 13 complete Irgm1 Autosomal mutation; C. trachomatis, L. monocytogenes, L. pneumophila, 22,52,61, complete M. bovis BCG, M. tuberculosis, S. Typhimurium, T. gondii, 95,102 T. cruzi Irgm2 Autosomal mutation; C. psittaci 58 complete Irgm3 Autosomal mutation; C. trachomatis, T. gondii 56,99 complete Irga6 Autosomal mutation; T. gondii 101 complete Irgb10 Autosomal mutation; C. trachomatis, C. psittaci 56,58 partial Irgd Autosomal mutation; T. gondii 95 complete Isg15 Autosomal mutation; HSV-1, murine gammaherpesvirus 68, influenza A 139 complete virus, Sindbis virus Mx1 Autosomal mutation; Influenza A virus, influenza B virus, Thogoto virus 128 complete or polymorphic Nos2 Autosomal mutation; C. trachomatis, coxsackie B3 virus, ectromelia virus, 7,39,41,91, complete L. major, L. monocytogenes, M. tuberculosis, P. yoelli, 93,94,144 S. Typhimurium, T. cruzi, T. gondii Prkra (encoding PKR) Autosomal mutation; Vaccina virus, West Nile virus 8 complete Rnasel (encoding Autosomal mutation; B. anthracis, E. coli, HSV-1, vaccinia virus, West Nile 8,165 RNase L) or OAS loci complete virus Rsad2 (encoding Autosomal mutation; West Nile virus 153 viperin) complete Slc11a1 (encoding Autosomal C. jejuni, L. donovani, L. major, M. avium, M. bovis BCG, 83 NRAMP1) mutation; complete S. Typhimurium or polymorphic G169D (Nramp1 ) AIEC, adherent invasive Escherichia coli; GBP, guanylate-binding protein; HBV57, hepatitis B virus 57; HCV, hepatitis C virus; IFITM, IFN-inducible transmembrane protein; IRG, immunity-related GTPase; ISG15, IFN-stimulated gene 15 kDa protein; MX1, myxovirus resistance 1; NOS2, nitric oxide synthase 2; NRAMP1, natural resistance-associated macrophage protein 1; OAS, 2ʹ-5ʹ oligoadenylate synthase; PKR, IFN-induced, RNA-activated protein kinase.*Other NADPH oxidase components are also affected (p47phox, p67phox ‡ § and p40phox). C. J. Bradfield and J.D.M., unpublished observations. A. R. Shenoy and J.D.M., unpublished observations. NATUR E R EVIEWS | IMMUNOLOGY VOLUME 12 | MAY 2012 | 371 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS mononuclear phagocytes produce lower NO level. s IRGs were first shown to target phagosomes and Experiments using NOS2 inhibitors that are relatively direct lysosomal membrane traffic in IFNγ-activated selective for this NOS isoform have implicated a role macrophages infected with M. tuberculosis . It is now for NO and its derivatives in the early cell-autonomous known that IRGs also exert membrane regulatory func - immune response to intracellular bacteria . This role was tions on other bacterial compartments, and their action further delineated in mice and macrophages deficient for has also been observed in human and mouse fibroblasts 39,40,41 51–54 NOS2 and/or gp91phox . M. tuberculosis is sensitive and epithelial cells . IRGs promote cell-autonomous to NO-mediated killing but relatively resistant to O immunity to vacuolar bacteria as diverse as M. tubercu- and H O , in part owing to its expression of the H O - losis, M. bovis, S. Typhimurium, Chlamydia trachomatis, 2 2 2 2 detoxifying enzyme KatG . NO exhibits molar potencies Chlamydia psittaci, Legionella pneumophila and Crohn’s comparable to the current antibiotics used to treat tuber- disease-associated adherent invasive Escherichia coli 22,23,51–61 culosis, and the tuberculocidal activity of some new drugs (AIEC) . Individual IRGs confer pathogen- (such as bicyclic nitroimidazoles) has been attributed to specific immunity in vitro and in vivo, indicating that their release of NO . By contrast, L. monocytogenes is they have non-redundant functions during host defence sensitive to O and H O but less vulnerable to NO, and (TABLE 2). Such specificity probably arises from the host- 2 2 2 S. enterica serovars are inhibited by both classes of chemi- derived interacting partners and trafficking pathways 39,41 cals . Such differences reflect the metabolic pathways used by a given IRG and the type of intracellular niche 18,19,51 and microbial DNA repair processes targeted by ROS and occupied by a given bacterial species . RNS, as well as the detoxifying systems expressed by the Recent studies have contributed to a conceptual bacteria (see TABLE 2). They may also reflect compar- t framework for how IRGs orchestrate immunity to dif- 21,23,53,54,59,60,62,63 mentalization; for example, L. monocytogenes becomes ferent compartmentalized pathogens . This sensitive to NO when trapped inside phagosomes, model posits co operative interactions between IRG sub- owing to synergism with other bactericidal insults or classes, as well as with SNARE proteins and autophagic the heightened RNS concentrations that accumulate in effectors that may disrupt the pathogen-containing a confined volume . Therefore, phagosomal escape of compartment before lysosomal delivery (FIG. 2) . L. monocytogenes before NOS2 recruitment could pro- IRGs are divided into two groups — GKS-containing vide a survival benefit for the pathogen. For this reason, IRGs and GMS-containing IRGs — based on their vertebrates have evolved other IFN-induced mechanisms canonical (lysine-containing) and non-canonical to deal with bacterial escapees, as discussed below. (methionine-containing) G1 motifs within the con- 18,19,51 served amino-terminal catalytic GTPase domain Lysosomal killing: phagosome maturation and (TABLE 1). IRGs in the GMS-containing subclass (IRGM1, autophagy. Acidified lysosomes are inimical for the IRGM2 and IRGM3 in mice; IRGM in humans) appear growth of most bacteria. Here, a low pH (~4.5–5.0) — to be intrinsic regulators that control the activities of which is generated via the action of proton-pumping their respective effectors, which can also include other 21,23,53,54,59,60,62,63 vacuolar ATPases and maintained with the assistance IRGs . For example, IRGM3 in the endo- of antiporters such as sodium/hydrogen exchanger 1 plasmic reticulum (ER) helps to maintain membran- o (NHE1) — enhances the bactericidal activity of both lytic GKS-containing IRGs (such as IRGA6 and possibly 7,9 ROS and RNS . In addition, an abundance of lumi- IRGB10) in the ‘off ’ state by acting as a non-canonical 62,63 nal proteases, lipases, glycosidases and antimicrobial guanine nucleotide dissociation inhibitor (GDI) . peptides contributes to the sterilizing power of ly- s When released from IRGM3, IRGA6 and IRGB10 45,46 osomes . This has resulted in some bacterial patho - directly target Chlamydia-containing inclusion bodies gens (such as M. tuberculosis) evolving strategies to avoid or disrupt the trafficking of sphingomyelin-containing 55,56 these degradative organelles, whereas other bacteria exocytic vesicles to these organelles . Such disruption (such as L. monocytogenes) try to escape into the cytosol. probably results in autophagic engulfment of the path- o 53 –/– –/– Stimulation of the infected cell with IFNγ prevents both gen and explains the susceptibility of Irgm3 , Irga6 Galectins 18,22,44 –/– of these evasion strategies . and Irgb10 fibroblasts to infection with C. trachomatis Lectins that bind a wide variety 52,56,58 At least two newly described families of IFN-inducible or C. psittaci . of glycoproteins and glycolipids containing GTPases — the 21–47 kDa immunity-related GTPases IRGM1 and its smaller constitutive human orthologue, β-galactoside. They have (IRGs) and the 65–73 kDa GBPs — traffic to vacuolar IRGM, engage their effectors when targeting M. tubercu- extracellular and intracellular and cytosolic bacteria, where they assemble membrane losis, M. bovis, S. Typhimurium, AIEC or early L. mono- functions, including the complexes to facilitate bacterial transfer to lysosomes cytogenes phagosomes as part of the IFNγ -induced regulation of apoptosis, RAS 16,18,19,21–23 21–23,51,54,57,59,60 signalling, cell adhesion and or disruption of the pathogen compartment . response to these bacteria . The translocation angiogenesis. IFN-inducible GTPases function together with three of IRGM1 to mycobacterial phagosomes involves the rec - ubiquitin-binding receptors — sequestosome 1 (SQSTM1; ognition of specific host phosphoinositide lipids (namely, SNARE proteins also known as p62), NDP52 and optineurin — that detect phosphatidylinositol -3,4,5-trisphosphate and, to a lesser (Soluble N-ethylmaleimide- ubiquitylated structures on bacteria, as well as wit h extent, phosphatidylinositol -3,4-bisphosphate) on the sensitive factor attachment protein receptor proteins). galectins that detect glycans that are exposed during nascent phagocytic cup (FIG. 2). Once recruited, IRGM1 A class of proteins that is bacterial escape into the cytosol. These receptors recruit interacts with and may regulate the assembly activity required for membrane fusion the autophagic machinery that engulfs bacteria for lyso - or phosphorylation status of snapin, a SNARE adaptor events that occur in the course 24,25,47–50 somal delivery . The resultant (auto)lysosomes kill protein that recruits dynein motor complexes to traffic of vesicle trafficking and secretion. and degrade the entrapped cargo. phagosomes and endosomes along microtubules towards 372 | MAY 2012 | VOLUME 12 w w w.nature.com/reviews/immunol © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS a Compartmentalized bacteria b Escaped cytosolic bacteria Bacterium Cytosol Disrupted PtdIns(4,5)P PtdIns(3,4,5)P 2 3 bacterial vacuole Ubiquitin IRGM1 Bacterial phagosome or inclusion body GBP2 SQSTM1 GBP1 GBP1 SQSTM1 Disruption? GBP7 LC3 Polymerization ATG4B IRGM3 IRGA6 or P Optineurin NDP52 LC3 IRGB10 Exposed P TBK1 IRGM1 LC3 glycans IRGM Snapin Galectin 3 ATG5 Autophagophore or galectin 8 engulfment LC3B Autophagophore Mitochondrion Cu 2+ Fe 2+ Mn ATP7A DAG NRAMP1 NOX2 Nucleus OH GBP7 or LRRK2 H H O 2 2 NO NOX2 PKCδ IFN-induced gene transcription AMPs NOS2 Autophagolysosome Autophagolysosome Figure 2 | Cell-autonomous mechanisms used by IFN-induced proteins against intracellular bacteria. Interferon (IFN)-inducible proteins are required for host resistance to intracellular bacteria. a | Specific immunity-related GTPases (IRGs), guanylate-binding proteins (GBPs) and other GTPases translocate to compartmentalized bacteria in phagosomes or inclusion bodies. Here, different membrane regulatory complexes — IRGM1–snapin, GBP1–sequestosome Nature Reviews | Immunology 1 (SQSTM1) and GBP7–ATG4B — are assembled. These complexes initiate autophagic capture and SNARE-mediated fusion of the 16,21–23 19,52,53 bacterial compartments with lysosomes . In addition, IRGM3–IRGA6 (or IRGB10) mediate vacuole disruption , and GBP7 (and possibly leucine-rich repeat kinase 2 (LRRK2)) help to assemble NADPH oxidase 2 (NOX2) on bacterial phagosomes, which mediates bacterial killing. Using this pathway, these GTPases can also deliver antimicrobial peptides (AMPs) to the autophagolysosome and, in the case of human IRGM, may instigate mitochondrial fission before autophagy . Other IFN-inducible components, such as natural resistance-associated macrophage protein 1 (NRAMP1), help to exclude 2+ 2+ + Mn and Fe from the bacterial phagosome, while importing protons (H ) into this compartment. Nitric oxide synthase 2 (NOS2), which synthesizes NO, works in concert with NOX2, which produces reactive oxygen species such as superoxide (O ) and hydrogen peroxide (H O ), to produce compound intermediates like peroxynitrite (not shown) that are highly 2 2 2 bactericidal. b | An emerging signature for the recognition of some escaped bacteria in the cytosol is ubiquitylation (either single or multiple modifications with monoubiquitin and/or polyubiquitin chains) (see REF. 47). SQSTM1, NDP52 and optineurin bind to ubiquitylated bacteria to initiate innate immune signalling and to recruit the autophagic machinery via LC3 family members. In addition, GBP1 and GBP2 polymerize around cytosolic bacteria in a ubiquitin-independent process that may recruit specific antimicrobial partners, while galectin 3 and galectin 8 bind to exposed glycans on the bacteria and, in the case of galectin 8, recruit NDP52 and downstream autophagic effectors . SQSTM1 also activates a second antibacterial pathway involving diacylglycerol (DAG) and protein kinase Cδ (PKCδ) to induce NOX2 complex assembly. Dashed lines indicate possible routes and consequences. PtdIns(4,5)P , phosphatidylinositol-4,5-bisphosphate; PtdIns(3,4,5)P , phosphatidylinositol-3,4,5-trisphosphate; TBK1, TANK-binding kinase 1. 21,64 maturing autolysosomes . Likewise, different human membranolytic, fusogenic and fission events in an indi- IRGM splice isoforms bind to the core autophagy proteins vidual cell. This accounts in part for why deficiencies in ATG5 and LC3B as well as the inner mitochondrial mem - GMS-containing IRGs cause such pronounced infectious brane lipid cardiolipin to induce mitochondrial fission phenotypes compared with those of GKS-containing 59,65 18,20,52,56–58 and autophagy ; these functions of IRGM may under- IRGs (TABLE 2). It may also explain why human lie its protective response to mycobacterial, Salmonella IRGM polymorphisms share genetic linkages with suscep - 23,54,59,60,65,66 spp. and AIEC infections . Thus, a single tibility to tuberculosis and Crohn’s disease across so many 66–69 GMS-containing IRG can act as a hub for coordinating geographically diverse populations . NATUR E R EVIEWS | IMMUNOLOGY VOLUME 12 | MAY 2012 | 373 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS In contrast to the IFN-inducible IRGs, GBPs target for binding ubiquitin and an internal or N-terminal escaped bacteria in addition to those residing within region that interacts with LC3 autophagy proteins 16,70,71 vacuoles . Nucleotide-dependent self-assembly of for delivering bacterial cargo to autophagic vacuoles some but not all GBPs — in which G domain dimers (FIG. 2; TABLE 1). Galactin 3 and galactin 8 contain pair with the carboxy-terminal helical domain (CTHD) carbohydrate-recognition domains, and galectin 8 to form GBP tetramers — helps to partition GBPs binds to NDP52, which links the recognition of sugar 16,72,73 between the cytosol and endomembranes of the cell moieties on bacteria with the autophagic machinery (P. Kumar and J.D.M., unpublished observations) further downstream (FIG. 2; TABLE 1). (TABLE 1). A C-terminal CaaX motif used for isoprenyla - NDP52 also recruits the IκB kinase (IKK) family 16,72–74 tion also contributes to this membrane attachmen t . kinase TBK1 (TANK-binding kinase 1) to ubiquitin- These structural features — along with an ability to o- li coated bacteria via the adaptor proteins SINTBAD gomerize with other GBPs or even interact with GMS- (also known as TBKBP1) and/or NAP1 (also known containing IRGs — dictate which endomembranes as AZI2) . TBK1 in turn phosphorylates optineurin to 16,72–76 individual GBPs occupy and aid GBP targeting to increase its affinity for ubiquitin; in this way, NDP52 both vacuolar and cytosolic bacteria (as the latter may and optineurin may cooperate to protect against 24,47 retain remnants of damaged host membrane on the sur- infection . Furthermore, NDP52 and SQSTM1 use face of their capsular coat following escape from the va-c septin- and actin-dependent autophagic pathways to uole) (C. J. Bradfield, P. Kumar and J.D.M., unpublished target cytosolic Shigella spp. and the small percentage 48,49 observations). This translocation of GBPs to bacteria of S. Typhimurium that escape their vacuole . By promotes intracellular defence againsL t . monocytogenes, contrast, autophagic delivery of non-motile L. monocy- S. Typhimurium, Chlamydia spp. and Mycobacterium togenes mutants occurs via a different, as yet unspeci- 16,70,71 49,50 spp. in both macrophages and epithelial cells . The fied, route . Because SQSTM1 activates a second lack of such cell-autonomous defence probably contr- ib antibacterial pathway involving diacylglycerol to induce –/– –/– 82 utes to the susceptibility of Gbp1 and Gbp5 mice to the assembly of NOX2 complexes , parallels may be bacteria (TABLE 2). drawn with the GBPs, which induce both oxidative The recent identification of interacting partners for and autophagic pathways to confer cell-autonomous GBP1 and GBP7 has begun to reveal the molecular host defence. mechanisms used by some of these GTPases to promote bacterial killig n . GBP1 interacts with the ubiquitin- Competing for intracellular cations. Facultative and binding protein SQSTM1, which delivers ubiquitylated obligate intracellular bacteria often have stringent metal protein cargo to autolysosomes, resulting in the genera - cation requirements for growth inside mammalian host tion of antimicrobial peptides that kill engulfeM. d bovis cells, which serve as a rich natural source of these chem -i 16,77,78 and L. monocytogenes . GBP7 recruits the autophagy cal elements. As a result, IFN-induced mechanisms have protein ATG4B, which drives the extension of autophagic evolved to restrict the intraphagosomal and cytosolic 2+ 2+ 2+ membranes around bacteria within damaged bacterial availability of Mn , Fe and Zn , and to enhance the + + compartments and assembles NOX2 on these compart- transport of Cu into the phagosome, as Cu helps to 16 83–85 ments (FIG. 2). GBP5, by contrast, binds NLRP3 (NOD-, drive the formation of microbicidal ROS . Indeed, 2+ 2+ LRR- and pyrin domain-containing 3) to promote specific the activation of macrophages by IFNγ lowers Mn , Fe 2+ + inflammasome responses during the infection of IFNγ- and Zn concentrations by ~2–6-fold and increases Cu activated macrophages by Listeria or Salmonella spp., levels by ~5 -fold within mycobacterial phagosomes . whereas in non-phagocytic cells heterotypic inte a rctions Part of the reduction in metal cation concentrations 2+ 2+ between GBPs may help to target cytosolic escaped bac - depends on a proton-dependent Mn and Fe efflux teria to autolysosomes (A. R. Shenoy, C. J. Bradfield and pump called natural resistance-associated macrophage J.D.M., unpublished observations). Thus, GBPs act in protein 1 (NRAMP1; encoded by Slc11a1), which is 83,87 concert — both temporally and physically — to confer upregulated by IFNγ . NRAMP1 prevents ion seques- their antibacterial effects. Moreover, they integrate oxi- tration specifically by phagosomal pathogens and com - dative, lysosomal and possibly inflammasome-relat ed petes with bacterial ion transporters for access to these killing as part of their host defence activities. nutritional metals (FIG. 2). For example, the growth In addition to being targeted by GBPs, cytosolic of S. Typhimurium mutants that lack mntH (which bacteria have recently been shown to encounter a sec- encodes an NRAMP1 homologue with a high affinity 2+ 2+ ond line of cell-autonomous defence orchestrated by for Mn and Fe ) or sitABCD (which encodes a second 2+ SQSTM1, NDP52, optineurin and galectins in mac- Mn -binding transport system) is attenuated in IFNγ- 24,25,47–50 rophages and epithelial cells . The IFN-inducible activated macrophages from mice that express the wild- proteins SQSTM1 and NDP52, along with basally type NRAMP1 efflux pump, but not in macrophages expressed optineurin, recognize bacteria coated with from congenic mice with a non-functional NRAMP1 G169D ubiquitin, whereas IFN-regulated galectins detect the efflux pump (derived from a defective Nramp1 β-galactoside moiety of polysaccharide sugars (host allele). Similarly, infection of macrophages by an glycans and microbial carbohydrates) that become M. tuberculosis strain lacking Mramp (another bacte- 2+ exposed on damaged membranes when bacteria escape rial NRAMP1 homologue) leads to increased Mn and 25,79–81 2+ their phagosome to reach the cytosol . SQSTM1, Fe concentrations within the phagosome, and this may NDP52 and optineurin all possess a C -terminal domain reduce bacterial viability . 374 | MAY 2012 | VOLUME 12 w w w.nature.com/reviews/immunol © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS IFNγ stimulation also regulates other cation In sum, synergistic IFN-inducible effector mecha- transport mechanisms, for example by inducing the nisms are deployed in the cytosol and in diverse intra - relocation of the P-type ATPase Cu pump ATP7A cellular compartments to control bacterial infection. For to the phagosome, where it can transport Cu across example, IRGs, GBPs and recognition receptors help to the membrane to promote the generation of intra- direct vacuolar bacteria as well as ‘marked’ cytosolic luminal hydroxyl radicals. This again leads to bacteria to acidified autophagolysosomes. Low lyso - intra phagosomal killing of bacteria. IFNγ stimulation somal pH, in turn, accelerates the dismutation of O to 2+ – concomitantly increases the expression of the Fe the more powerful oxidant H O , converts NO back 2 2 2 exporter ferroportin 1 (also known as SLC40A1) at to the toxic radical NO and drives hydroxyl radicaf lor- the plasma membrane, while decreasing transferrin mation with the aid of imported Cu . Together, these 2+ receptor expression to limit Fe uptake; both mecha- IFN-regulated proteins help to maximize oxidative, nisms further restrict the growth of S. Typhimurium nitrosative, protonative and membranolytic damage to in macrophages . bacterial targets in the lysosome. Cell-autonomous defence against protozoa In vertebrates, many protozoa are obligate intracell- u Parasite lar pathogens that depend on the host cell for specific amino acids and metal ions. The nutritional and safety needs of different parasites often dictate the type of compartment they inhabit (reviewed in REF. 90). For example, the apicomplexan parasite Toxoplasma gondii (which causes human toxoplasmosis) occupies a non- fusogenic vacuole that excludes most host-derived pro - Parasitophorous teins, whereas the kinetoplastid parasites Trypanosoma vacuole cruzi (which is responsible for Chagas disease) and IRGB6 Leishmania spp. (which trigger cutaneous, mucocuta- l -tryptophan IDO IRGB10 IRGA6 neous and visceral leishmaniasis) reside in the cytosol and in modified lysosomes, respectivel y . These strat- IRGA6 IRGD N-formyl- egies operate effectively in resting cells by allowing kynurenine the parasites access to nutrients while helping them to avoid contact with many host microbicidal proteins. GBP1 However, once cells become stimulated with IFNs, new ATG5 GBP5 GBP2 host defence pathways are transcriptionally induced to Parasitophorous help limit parasite infection. disruption Autophagophore IRGM1 IRGM2 IRGM3 Parasiticidal activities. Previous studies have high- lighted the role of NOS2 -mediated killing in cell- 2+ Fe Necroptosis 2+ autonomous defence against a variety of protozoa Mn (reviewed in REF. 7). The parasiticidal effects of NO are most evident in IFNγ- activated macrophages infected NRAMP1 Nucleus with Leishmania major amastigotes or T. cruzi trypo- mastigotes and in human and mouse hepatocytes infected with Plasmodium falciparum and Plasmodium 91–93 yoelli sporozoites, respectively (FIG. 3). Furthermore, NO –/– IFN-induced Nos2 mice were highly susceptible to these patho - gene transcription 91–93 NOS2 gens (TABLE 2). In the case of less virulent type II T. gondii tachyzoites, IFN-inducible NOS2 plays a more Autophagolysosome limited part, functioning at later time points after the IFN-inducible GTPases have contained parasite growth Figure 3 | Cell-autonomous mechanisms used by IFN-induced proteins against during the early stages of infection . For virulent type I intracellular protozoa. Different intracellular strategies are used by interferon Nature Reviews | Immunology (IFN)-inducible proteins against protozoa. Nitric oxide synthase 2 (NOS2) exerts T. gondii strains, however, NOS2 is essential, because potent parasiticidal activity, while GKS-containing immunity-related GTPases (IRGs) these parasites have evolved mechanisms to escape IRG- appear to be directly involved in parasite vacuole disruption once they reach the mediated inhibition in IFNγ-activated macrophages . parisitophorous compartment. This proceeds via autophagy-independent trafficking Here, NO does not appear to eliminate virulent T. gondii after release from IRGM1–IRGM3 or ATG5 and is mediated by cooperative IRG but instead imposes static, non-lethal control. How 62,63,103 loading . Guanylate-binding proteins (GBPs) — specifically GBP1–GBP2 and NO inhibits Toxoplasma parasites, along with malaria, GBP1–GBP5 complexes — also traffic to the parasitophorous vacuole, with Leishmania and Trypanosoma parasites, remains incom- uncharacterized effects on parasite control . Natural resistance-associated 2+ pletely understood, but haem-containing compounds macrophage protein 1 (NRAMP1) is important for restricting the uptake of Mn and 2+ (such as haemozoin) and protozoal cysteine proteases Fe by this compartment, whereas indoleamine 2,3 -dioxygenase 1 (IDO1) and/or appear to be likely targets for S-nitrosylation, which can IDO2 limit amino acid acquisition via the depletion of l -tryptophan. Dashed lines indicate possible routes or consequences. inactivate these enzymes . NATUR E R EVIEWS | IMMUNOLOGY VOLUME 12 | MAY 2012 | 375 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS Targeting the parasitophorous vacuole. As in the case T. gondii, Leishmania spp. and Chlamydia spp. in humans of bacteria, IFN-inducible IRGs and GBPs defend is often superseded by the NOS2 pathway in other species the interior of the host cell against protozoa. IRGM1, (such as mice and rats), in which NOS2 may represent a 7,108,111 IRGM3 and IRGA6 promote IFNγ-induced control more robust front-line defence mechanism . (but not TNF- or CD40-dependent control) of avirulent Overall, the relative potencies of NOS2, IDOs, IRGs 96–101 T. gondii in macrophages and astrocytes . IRGM1 and GBPs against protozoa reflect not only the species- also contributes to macrophage trypanocidal activity specific pathways available in vertebrates but also the (TABLE 2). Inhibition of avirulent T. gondii appears to co-evolutionary adaptations used by different parasites rely on several IRGs, with IRGM proteins providing a to survive within vertebrate host cells. regulatory function by acting as GDIs that release GKS- containing IRGs to target the parasitophorous vacuole Cell-autonomous defence against viruses (FIG. 3). Recent studies invoke a hierarchical model in Viruses were the first reported targets of IFN-mediated which IRGB6 and possibly IRGB10 act as forerunners immunity, and they are the one taxonomic group that to IRGA6 and then IRGD during their loading onto the can infect all nucleated cells (reviewed in REF. 8). Less parasitophorous vacuole some 90 minutes after parasite complex than eukaryotic protozoa and considerably entry. The recruitment of these molecules is followed smaller than most bacteria in terms of size and genome by vesiculation, membrane disruption and sometimes content, viruses nonetheless represent a major challenge 62,63 necroptosis . What remains unknown are the struc- to the host owing to their high mutation rates (up to –8 tural and biochemical cues for targeting these molecules 10 mutations per base per generation), their diverse to the parasitophorous vacuole and whether membrane cell tropisms and their ability to co-opt the replication deformation is directly due to IRG activity or a result of machinery of the cell. For these reasons, IFN-inducible some intermediary protein. These are topics of future proteins operate in multiple cell types and at all s -uc investigation. cessive stages of the viral life cycle, including entr y, Other proteins assist the relocation of IRGs to the replication, capsid assembly and release. parasitophorous vacuole. For example, ATG5 facilitates the release and transit of IRGA6 from its bound state . Blocking viral entry and uncoating. At least two IFN- Heterotypic interactions between different GBPs have inducible protein families have recently been shown also recently been shown to underlie the vacuolar targ- et to interfere with viral entry and uncoating: the IFN- ing of GBPs (FIG. 3). Hence, multiple parasitophorous inducible transmembrane (IFITM) proteins and the vacuole-damaging mechanisms are likely to ensue as the tripartite motif (TRIM) proteins. IRGs and GBPs converge on this organelle. Because viru - IFITM1, IFITM2 and IFITM3 restrict the entry and lent T. gondii strains (but not avirulent strains) exclude endosomal fusion of influenza A virus and flaviviruses 76,104,105 IRGs and GBPs from the parasitophorous vacuole , (such as West Nile virus and dengue virus) in both it is likely that these IFN-inducible GTPases exert a IFNγ- and IFNα-treated human cells . Recent studies strong selective pressure via their membrane regula - also extend the antiviral profile of these three IFITMs tory activities. Such pressure appears to be specific for to include HIV -1, coronaviruses and the Marburg and 114–116 different protozoa, as GBP1 is not recruited to T. cruzi Ebola filoviruses . In the case of IFITM3, a C-terminal compartments . transmembrane region and S-palmitoylation contribute to its antiviral activity in membrane-bound compartments 115–119 Restricting nutrient acquisition. Nutriprive mechanisms such as late endosomes and lysosomes (TABLE 3). are particularly effective against parasites. NRAMP1 IFITM3 is thought to deny cytosolic access to influ - prevents ion assimilation by Leishmania spp. (L. major enza A virus by preventing viral genomes from leaving th e 83 119 and L. donovani) and indoleamine 2,3 -dioxygenases endocytic pathway (FIG. 4). (IDOs) hamper amino acid acquisition . IDO1 and TRIMs also serve as viral restriction factors, particularly IDO2 are both IFN-inducible, haem-containing oxi- against retroviruses such as HIV-1. In vertebrates, many doreductases that are responsible for the initial rate- TRIMs are induced by IFNs (primarily by type I IFNs) in limiting step of the kynurenine pathway, in which they macrophages, myeloid dendritic cells, peripheral blood degrade l-tryptophan to generate N-formylkynurenine lymphocytes and fibroblasts . TRIM-dependent antiviral (FIG. 3; TABLE 1). Removal of l-tryptophan restricts the activity relies on a shared N-terminal RING domain that growth of Leishmania spp. and T. gondii (as well as that functions as an E3 ligase and/or on a C-terminal SPRY 120,121 of C. psittaci, Francisella spp., Rickettsia spp., herpes domain that enables protein–protein interactions simplex virus 1 and hepatitis B virus) in IFNγ-activated (TABLE 3). TRIM5α can restrict HIV-1 entry by binding to macrophages, dendritic cells, fibroblasts, epithelial the retroviral capsid to accelerate its cytoplasmic uncoating cells, astrocytes, endothelial cells and mesenchymala nd, as demonstrated more recently, by activating innate 107–111 stem cells . IDOs also inhibit T. cruzi via the down- immune signalling through associations with the E2 stream l-kynurenine catabolites 3-hydroxykynurenine ubiquitin-conjugating enzyme complex UBC13–UEV1A and 3-hydroxyanthranilic acid, which are likely to be (also known as UBE2N–UBE2V1), which activates TGF β- 112 122,123 toxic for T. cruzi amastigotes and trypomastigotes . activated kinase 1 (TAK1) to induce immune genes . Furthermore, in vivo blockade of IDOs using 1-methyl- Which of these two mechanisms predominates is as yet tryptophan results in profound host susceptibility to unresolved. In addition, TRIM22 combats hepatitis B T. gondii . This host-protective role of IDOs against virus and encephalomyocarditis virus by interfering with 376 | MAY 2012 | VOLUME 12 w w w.nature.com/reviews/immunol © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS pre-genomic RNA synthesis and protease activity, whereas The myxoma resistance proteins (MXs) are also IFNβ-inducible TRIM79α restricts tick-borne encephalitis antiviral effector molecules involved at an early stage virus by mediating the lysosomal degradation of the viral in type I IFN- and IFNλ-induced host defence against RNA-dependent RNA polymerase NS5 (REFS 124–126). orthomyxoviruses (such as influenza and Thogoto TM 128 Furthermore, IFNα-inducible TRIM21 delivers incoming viruses), bunyaviruses, togaviruses and rhabdo viruses . TM CD225 CD225 TM IgG-bound adenovirus to the proteasome through its E3 Human and mouse MX1, as well as mouse MX2, CD225 CD225 TM 127 CD225 CD225 128,129 ubiquitin ligase activity . Thus, the number of different exhibit antiviral activity . Mouse MX1 localizes to CD225 CD225 CBD CD225 CD225 TM CD225 CD225 CBD effector mechanisms used by members of the TRIM family promyelocytic leukaemia (PML) nuclear bodies and CD225 CD225 CBD CD225 CD225 CD225 TM CD225 CBD continues to grow. restricts nuclear viruses, whereas both human MX1 CD225 CD225 R BB1 BB2 CC COS FN3 PRY SPRY CD225 TM CD225 CBD R BB1 BB2 CC COS FN3 PRY SPRY CD225 CD225 R BB1 BB2 CC COS FN3 PRY SPRY CD225 TM CD225 CBD TM R BB1 TM TMBB2 CC COS FN3 Table 3 | Repertoire of IFN-induced antiviral effectors R BB1 BB2 CC COS FN3 PRY SPRY R BB1 BB2 CC COS FN3 CD225 CD225 CD225 CD225 CD225 CD225 CD225 CD225 CD225 CD225 CBD R BB1 BB2 CC COS FN3 R BB1 BB2 CC PRY SPRY IFN-induced Name Domain structur R BB1 TMBB2 e CC COS FN3 PRY SPRY R BB1 BB2 CC COS FN3 R BB1 BB2 CC PRY SPRY TM TM CD225 CD225 CBD effector family CD225 TM TM CD225 CBD RCD225 CD225 CD225 BB1 BB2 CD225 CD225 CD225 CC CBD CBD PRY SPRY TM TM TM R R BB1 BB1 BB2 BB2 CC CC COS FN3 PRY SPRY TM COS FN3 R BB1 TM TM TMBB2 CC RCD225 CD225 BB1 BB2 CD225 CD225 CC PRY SPRY CD225 CD225 CD225 CD225 RCD225 CD225 BB1 BB2 CD225 CD225 CC CD225 TM TM CD225 IFITM family IFITM1, IFITM2 or IFITM3 CD225 CD225 CD225 CD225 R RCD225 CD225 CD225 BB1 BB1 BB2 BB2 CD225 CD225 CD225 CC CC COS CBDFN3 PRY SPRY R BB1 BB2 CC PHD BR R BB1 BB2 CC COS FN3 R BB1 BB2 CC PRY SPRY RCD225 CD225 BB1 BB2 CD225 CD225 CC CD225 CD225 CD225 CD225 CBD CBD PHD BR RCD225 CD225 BB1 BB2 CD225 CD225 CC CBD CBD CD225 CD225 CD225 CD225 CBD CBD CD225 CD225 CBD R BB1 BB2 CC COS PHD FN3 BR PRY SPRY R RCD225 BB1 BB1 BB2 BB2 CD225 CC CC COS CBDFN3 PRY SPRY R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 P PRY RY SPR SPRY Y RCD225 CD225 CD225 BB1 BB2 CD225 CD225 CD225 CC COS FILCBD CBD CBDNHL FN3 R R BB1 BB1 BB2 BB2 CC CC PRY SPRY R BB1 BB2 CC R BB1 BB2 CC PHD BR IFITM5 CD225 CD225 CD225 CD225 CBD CBD NHL R BB1 BB2 CC FIL COS NHL FN3 R R BB1 BB1 BB2 BB2 CC CC FIL R R BB1 BB1 BB2 BB2 CC CC COS COS COS FN3 FN3 FN3 PRY SPRY R R R R BB1 BB1 BB1 BB1 BB2 BB2 BB2 BB2 CC CC CC CC COS ARF FN3 PRY SPRY PHD BR R R BB1 BB1 BB2 BB2 CC CC FIL NHL R BB1 BB2 CC TRIM family Subfamily TRIM C-I R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 P PRY RY SPR SPRY Y R BB1 BB2 CC ARF R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 P PRY RY SPR SPRY Y R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 P PRY RY SPR SPRY Y R R BB1 BB1 BB2 BB2 CC CC COS FN3 P PRY RY SPR SPRY Y R R BB1 BB1 BB2 BB2 CC CC ARF PRY SPRY R R R R R BB1 BB1 BB1 BB1 BB1 BB2 BB2 BB2 BB2 BB2 CC CC CC CC CC COS PHD FN3 P P PRY RY RY SPR SPR SPRY Y Y PHD BR R R R R R BB1 BB1 BB1 BB1 BB1 BB2 BB2 BB2 BB2 BB2 CC CC CC CC CC COS COS COS COS FN3 FN3 FN3 FN3 P P PRY RY RY SPR SPR SPRY Y Y R BB1 BB2 CC FIL NHL R BB1 BB2 CC ARF R BB1 BB2 CC PHD Subfamily TRIM C-III R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 P PRY RY SPR SPRY Y R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 R BB1 BB2 CC PHD R R R BB1 BB1 BB1 BB2 BB2 BB2 CC CC CC COS COS FN3 FN3 R R RR BB1 BB1 BB1 BB2 BB2 BB2 BB2 CC CC CC CC COS PHD COS FN3 BR R R BB1 BB1 BB2 BB2 CC CC R R BB1 BB1 BB2 BB2 CC CC COS NHL FN3 PRY SPRY R BB1 BB2 CC COS FIL FN3 R R R R BB1 BB1 BB1 BB1 BB2 BB2 BB2 BB2 CC CC CC CC COS COS ARF FN3 FN3 R BB1 BB2 CC PHD R BB2 CC COS R R BB1 BB1 BB2 BB2 CC CC P PRY RY SPR SPRY Y Subfamily TRIM C-IV R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 R R BB1 BB1 BB2 BB2 CC CC P PRY RY SPR SPRY Y R R RR BB1 BB1 BB1 BB2 BB2 BB2 BB2 CC CC CC CC PHD COS BR P PRY RY SPR SPRY Y R R BB1 BB1 BB2 BB2 CC CC PHD BR PRY SPRY R R R BB1 BB1 BB2 BB2 BB2 CC CC CC MA PHD PHD FILTHNHL BR BR R R BB1 BB1 BB2 BB2 CC CC PRY SPRY R BB1 BB2 CC ARF R R R R R BB1 BB1 BB1 BB1 BB1 BB2 BB2 BB2 BB2 BB2 CC CC CC CC CC PHD P P PRY RY RY SPR SPR SPRY Y Y R BB2 CC COS R BB2 CC MATH R R R BB1 BB1 BB1 BB2 BB2 BB2 CC CC CC P PRY RY SPR SPRY Y R BB1 BB2 CC Subfamily TRIM C-V R BB1 BB2 CC R BB1 BB2 CC R R R BB1 BB1 BB2 BB2 BB2 CC CC CC MA FILTHNHL R BB1 BB2 CC FIL NHL R R R R R BB1 BB1 BB1 BB1 BB1 BB2 BB2 BB2 BB2 BB2 CC CC CC CC CC ARF FIL FIL NHL NHL R BB1 BB2 CC PHD PHD BR R R RR BB1 BB1 BB2 BB2 BB2 BB2 CC CC CC CC COS R R BB1 BB1 BB2 BB2 CC CC R R BB1 BB2 BB2 CC CC MATH R R BB1 BB1 BB2 BB2 CC CC PHD PHD BR BR R BB1 BB2 CC R R R BB1 BB1 BB2 BB2 BB2 CC CC CC PHD PHD BR BR R BB1 BB2 CC Subfamily TRIM C-VI R BB1 BB2 CC PHD PHD BR BR R R R BB1 BB1 BB1 BB2 BB2 BB2 CC CC CC PHD ARF BR R R BB1 BB1 BB2 BB2 CC CC PHD ARF R R R BB1 BB1 BB2 BB2 BB2 CC CC CC PHD ARF ARF BR RR BB1 BB2 BB2 CC CC COS NHL R R R R R BB1 BB1 BB1 BB1 BB2 BB2 BB2 BB2 BB2 CC CC CC CC CC MA PHD PHD PHD FILTH BR BR BR R BB2 CC R BB1 BB2 CC PHD PHD FIL NHL NHL BR BR R R R BB1 BB1 BB1 BB2 BB2 BB2 CC CC CC FIL FIL NHL NHL R R BB1 BB1 BB2 BB2 CC CC FIL Subfamily TRIM C-VII R BB1 BB2 CC PHD FIL NHL NHL R R RR BB1 BB1 BB1 BB2 BB2 BB2 BB2 CC CC CC CC PHD COS FIL NHL R R R BB1 BB1 BB1 BB2 BB2 BB2 CC CC CC PHD PHD FIL R R R BB1 BB1 BB2 BB2 BB2 CIDCC CC CC MA ARF FILTHNHL R BB1 BB2 CC FIL FIL NHL NHL NHL R R BB1 BB1 BB2 BB2 CC CC FIL R BB2 CC DYN LZ R R BB1 BB1 BB2 BB2 CIDCC CC ARF ARF FIL NHL NHL R R BB1 BB1 BB2 BB2 CC CC FIL R R BB1 BB1 BB2 BB2 CC CC ARF ARF R BB2 CC COS RR BB1 BB2 BB2 CC CC ARF COS Subfamily TRIM C-IX R R RR R BB1 BB1 DYN BB2 BB2 BB2 BB2 BB2 CIDCC CC CC CC CC LZMA ARF ARF COS COS TH R BB1 BB2 CC PHD R BB1 BB2 CC ARF R R R R BB1 BB1 BB1 BB2 BB2 BB2 BB2 CC CC CC CC ARF ARF ARF DYN LZ CID R R BB1 BB1 BB2 BB2 CC CC PHD PHD R BB1 BB2 CC ARF R R R BB1 BB1 BB1 BB2 BB2 BB2 CC CC CC PHD PHD ARF DYN LZ R R R BB1 BB1 BB2 BB2 BB2 CC CC CC MA PHD PHD TH R BB1 BB2 CC PHD R R R BB2 BB2 BB2 CC CC CC MA MA MATH TH TH Subfamily TRIM C-X R RR BB1 BB2 BB2 BB2 CC CC CC PHD COS R R R BB1 BB1 BB1 BB2 BB2 BB2 CC CC CC PHD PHD PHD CID R R BB2 BB2 CC CC COS COS R R BB1 BB1 BB2 BB2 CC CC PHD PHD R DYN BB2 CC LZCOS R BB2 CC COS R OAS1 BB2 CC COS R R BB2 BB2 CC CC COS COS R BB2 CC RR BB2 BB2 CC CC COS Subfamily TRIM C-II R R RR R R BB2 BB2 BB2 BB2 BB2 BB2 CC CC CC CC CC CC MA COS COS COS TH CID OAS1 R DYN BB2 CC LZCOS R RR BB2 BB2 BB2 CC CC CC MA MA COS TH TH R OAS1 CC MATH R BB2 BB2 CC MATH OAS2.1 OAS2.2 R R BB2 BB2 CC CC MA MATH TH R BB2 CC MATH R OAS1 BB2 CIDCC MATH Subfamily TRIM C-VIII R BB2 CC MATH R R R BB2 BB2 BB2 CC CC CC MA MATH TH OAS2.1 OAS2.2 DYN LZ R R BB2 BB2 CC CC MA MATH TH R R OAS2.1 BB2 BB2OAS2.2 CC CC R R BB2 BB2 CC CC OAS3.1 OAS3.2 OAS3.3 R OAS1 BB2 CIDCC R R BB2 BB2 CID CIDCC CC OAS2.1 OAS2.2 CID Subfamily TRIM C-XI R BB2 CC R R R DYN BB2 BB2 BB2 CC CC CC LZ OAS3.1 DYN OAS3.2 OAS3.3 LZ DYN DYN LZ LZ R R OAS3.1 BB2 BB2OAS3.2 CC CC OAS3.3 OAS1 OAS2.1 OASL UBL OAS2.2 OAS3.1 OAS3.2 CID OAS3.3 MX family MX1 or MX2 OASL DYN UBL LZ CID CID OAS1 CID CID OASL UBL OAS2.1 OAS2.2 CID CID DYN DYN CID LZ LZ OAS3.1 OAS3.2 OAS3.3 DYN DYN CID LZ LZ CID OASL DYN DYN UBLCID CID LZ LZ DYN LZ OAS family OAS1 DYN LZ OAS1 DYN DYN DYN LZ LZ LZ OAS1 CID CID OAS2.1 OAS1 OAS1 OAS2.2 OAS3.1 OAS3.2 OAS3.3 DYN DYN LZ LZ RBM1 RBM2 S/T-kinase OASL UBL RBM1 OAS2.1RBM2 OAS2.2 S/T-kinase OAS2 OAS2.1 OAS2.1 OAS2.1 OAS2.2 OAS2.2 OAS2.2 OAS3.1 OAS3.2 OAS3.3 OAS1 RBM1 RBM2 S/T-kinase OASL UBL OAS1 RBM1 OAS1 RBM2 S/T-kinase OAS1 OAS1 OAS1 OAS1 OAS3.1 OAS1 OAS3.2 OAS3.3 OAS3 OAS3.1 OAS3.2 OAS3.3 OAS3.1 OAS3.1 OAS1 OAS3.2 OAS3.2 OAS3.3 OAS3.3 OAS2.1 OAS1 OAS1 OAS1 OASL UBL OAS2.2 ANK RBM1 RBM2 S/T-kinase OAS1 OAS2.1 OAS2.1 OAS1 OAS2.2 OAS2.2 OAS2.1 ANK OAS2.2 OAS2.1 OAS2.2 OAS2.1 OAS2.2 STYK PUG OAS2.1 OAS2.2 OAS2.1 OAS2.2 OASL ANK UBL OASL OAS2.1 UBL OAS2.2 OAS2.1 OAS2.1 OAS3.1 OASL OASL OASL UBL UBL OAS2.2 OAS2.2 OAS3.2 OAS3.3 OAS2.1 OAS2.2 STYK PUG RBM1 RBM2 S/T-kinase ANK OAS2.1 OAS2.2 OAS2.1 OAS3.1 OAS3.1 OAS2.2 STYK OAS3.2 OAS3.2PUGOAS3.3 OAS3.3 OAS3.1 OAS3.1 OAS3.2 OAS3.2 OAS3.3 OAS3.3 OAS3.1 OAS3.1 OAS3.2 OAS3.2 OAS3.3 OAS3.3 OAS3.1 OAS3.2 OAS3.3 STYK PUG PKR EIF2AK OAS3.1 OAS3.2 OAS3.3 RBM1 OAS3.1 OAS3.1 OAS3.1RBM2 OAS3.2 OAS3.2 OAS3.2 S/T-kinase OAS3.3 OAS3.3 OAS3.3 OASL ANK UBL OAS3.1 OAS3.1 OAS3.2 OAS3.2 OAS3.3 OAS3.3 UBL OASL OASL UBL OASL UBL OASL ZF1 UBL CD STYK PUG ZF2 CD OASL UBL OASL UBL RBM1 OASL RBM2 UBL S/T-kinase RBM1 RBM2 S/T-kinase RBM1 RBM1 OASL ANK RBM2 RBM2 UBL S/T S/T-kinase -kinase OASL UBL UBL RNase L RNAseL OASL OASL UBL ZF1 CD ZF2 CD UBL OASL OASL ZF1 UBL CD ZF2 CD STYK PUG ANK ZF1 CD ZF2 CD RBM1 RBM2 S/T-kinase STYK PUG RBM1 RBM2 S/T-kinase RBM1 SAM RBM2 HD S/T-kinase RBM1 RBM2 S/T-kinase APOBEC3 APOBEC3 RBM1 ANK RBM2 S/T-kinase RBM1 ANK ZF1 RBM2 CD S/T ZF2 -kinaseCD RBM1 ANK ANK RBM2 S/T-kinase RBM1 RBM2 S/T-kinase RBM1 SAM RBM2 HD S/T-kinase RBM1 RBM1 RBM2 RBM2 S/T S/T-kinase -kinase RBM1 RBM2 S/T-kinase STYK PUG SAM STYK HD PUG STYK STYK PUG PUG RBM1 RBM2 S/T-kinase RBM1 RBM2 S/T-kinase ZF1 CD ZF2 CD SAMHD1 SAMHD1 SAM HD ANK UBL UBL ANK ANK UBL ANK ANK ZF1 UBL CD STYK PUG ZF2 CD SAM ANK ANK HD ANK ISG15 ISG15 UBL ANK UBL ANK ANK ANK STYK STYK PUG PUG STYK STYK PUG PUG STYK STYK PUG PUG UBL TM UBL STYK PUG ANK ANK ZF1 CD ZF2 CD ZF1 CD STYK PUG ZF2 CD ZF1 ZF1 CD CD STYK PUG ZF2 ZF2 CD CD SAM STYK STYK HD PUG PUG TM Tetherin Tetherin CYD STYK STYKCC PUG PUG UBL TM UBL CYD SAM HD CC TM ZF1 CD ZF2 CD CYD CC UBL ZF1 ZF1 UBL CD CD ZF2 ZF2 CD CD ZF1 CD ZF2 CD CYD ZF1 CD CC ZF2 CD SAM ZF1 CD HD ZF2 CD SAM ZF1 ZF1 TMCD CD HD ZF2 ZF2 CD CD SAM SAM HD HD Viperin Viperin SAM ZF1 CD ZF2 CD ZF1 ZF1 ZF1 CD CD CD ZF2 ZF2 ZF2 CD CD CD UBL UBL SAM ZF1 CD ZF2 CD CYD ZF1 CD CC ZF2 CD TM SAM SAM HD Family and domain organization of the major IFN-induced antiviral effectors (see REF. 8). ANK, ankyrin repeats; APOBEC3, UBL UBL UBL SAM UBL UBL UBL UBL UBL CYD SAM SAM HD HD CC apolipoprotein B mRNA-editing enzyme, catalytic polypeptide 3; ARF, SAM SAM ADP ribosylation HD HD factor; BB, B-box; BR, bromodomain; CBD, TM SAM SAM HD HD SAM HD SAM HD 2+ SAM SAM SAM HD HD HD Ca -binding domain; CC, coiled-coil domain; CD, cytidine deaminase SAM domain; CID, central interactive domain; COS, C- terminal CYD CC Nature Reviews | Immunology UBL SAM SAM UBL HD HD TM TM subgroup one signature; CYD, cytoplasmic domain; DYN, dynamin-like domain; TM TM EIF2AK, eukaryotic translation initiation factor 2α UBL UBL UBL UBL Nature Reviews | Immunology UBL UBL SAM UBL UBL kinase; FN3, fibronectin type 3; FIL, filamin-type immunoglobulin; HD, UBL UBL CYD helical domain; UBL UBL CC IFITM, interferon-inducible transmembrane UBL CYD UBL CC Nature Reviews | Immunology CYD CYD CC CC UBL UBL UBL UBL UBL UBL UBL UBL Nature Reviews | Immunology protein; ISG15, IFN-stimulated gene 15 kDa protein; LZ, leucine zipper; MATH, TM meprin and TNFR-associated factor homology; MX, UBL UBL SAM UBL UBL TM TM myxoma resistance protein; NHL, NHL repeat; OAS, 2ʹ-5ʹ oligoadenylate synthetase domain (catalytically inactive domains shown TM TM CYD CC TM TM TM Nature Reviews | Immunology TM in grey); P, palmitoylation site; PHD, plant homeodomain; PKR, IFN-induced, SAM RNA-activated TM TM TM protein kinase; PUG, protein kinase CYD CYD SAM CC CC SAM SAM CYD CYD CC CC CYD CYD CC CC CYD TM TM CC domain (containing a UBA or UBx domain); R, RING domain; RBM, RNA binding motif; SAM, radical S-adenosyl methionine domain; CYD CC CYD CYD CYD CC CC CC Nature Reviews | Immunology SAMHD1, SAM-domain- and HD-domain-containing protein 1; STYK, CYD CYD Ser/Thr/Tyr kinase CC CC domain; TM, transmembrane domain; SAM Nature Reviews | Immunology TRIM, tripartite motif protein; UBL, ubiquitin-like domain, ZF, zinc finger. SAM SAM SAM SAM SAM SAM SAM SAM SAM SAM SAM Nature Reviews | Immunology Natur Natur Nature Re e Re e Reviews views views ||| Immunology Immunology Immunology SAM SAM Nature Reviews | Immunology NATUR E R EVIEWS | IMMUNOLOGY VOLUME 12 | MAY 2012 | 377 Natur Nature Re e Reviews views || Immunology Immunology Natur Nature Re e Reviews views || Immunology Immunology Natur Nature Re e Reviews views || Immunology Immunology Nature Reviews | Immunology Nature Reviews | Immunology Nature Reviews | Immunology Natur Nature Re e Reviews views || Immunology Immunology © 2012 Macmillan Publishers Limited. All rights reserved Natur Nature Re e Reviews views || Immunology REVIEWS replication . Results from recent crystallography expe -r Virus iments suggest that disordered loops within an elongated Viral release MX1 helical ‘stalk’ may dock with negatively charged nucleocapsids to mediate entrapment . Viral entry Structural analogies with the MX proteins could also Tetherin underpin the antiviral activity reported for dynamin- like GBPs against vesicular stomatitis virus (VSV), IFITMs encephalomyocarditis virus, hepatitis C virus and 18,131 influenza A virus . Human GBP1, GBP3 and a novel Endosome Viral assembly splice isoform termed GBP3ΔC (which lacks part of or lysosome the C-terminal helical domain) (TABLE 1) appear to be Viperin dependent on GTP binding but not hydrolysis for their effects, suggesting that oligomerization is important for Uncoating ISG15 the antiviral activity of GBPs. This evolutionary adap - tation may allow GBPs to avoid viral antagonists such TRIM5α as the NS5B protein of hepatitis C virus, which can interfere with their catalytic activity . Protein APOBEC3 translation MXs Inhibiting viral replication. Once viruses uncoat, they SAMHD1 establish cytoplasmic or nuclear sites of replication RNA reverse transcription (which for Retroviridae includes chromosomal inte - PKR or gration). The landmark discoveries of IFN-induced, NOS2 RNA-activated protein kinase (PKR) and 2ʹ-5ʹ oligo- Nucleus adenylate synthase 1 (OAS1), OAS2 and OAS3 (and OASL in humans) provided early insights regard- GBP3ΔC RNA ing how viral RNA substrates are targeted (reviewed transcription in REF. 8). PKR possesses RNA-binding motifs at its RNase L Retroviral or ISG20 N-terminus that engage both double-stranded RNA integration Viral RNAs (dsRNA) and single-stranded RNA (ssRNA) (TABLE 3); the viral uncapped RNAs that are recognized by PKR NOS2 OAS ADAR1 often have limited duplexed regions and 5 ʹ triphosphate moieties, which enable the enzyme to distinguish them Figure 4 | Cell-autonomous mechanisms used by IFN-induced proteins against from host, capped RNA species . Once activated, PKR viruses. Multiple strategies are used by interferon (IFN)-inducible proteins to combat Nature Reviews | Immunology phosphorylates eukaryotic translation initiation fac - viruses. IFN-inducible effectors function at nearly every stage of the pathogen life tor 2α (EIF2α) to block viral and host protein tran- s cycle. For example, interferon-inducible transmembrane proteins (IFITMs) and lation, a process that is thought to be under intense tripartite motif proteins (TRIMs) act during viral entry and uncoating, and myxoma resistance proteins (MXs) block nucleocapsid transport. Inhibition of RNA reverse positive selection to avoid the emergence of viral mim - transcription, protein translation and stability is mediated by APOBEC3 ics of the substrate EIF2α . Likewise, the recognition (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide 3), SAMHD1 of dsRNA by OAS enzymes results in the production (SAM-domain- and HD-domain-containing protein 1), ADAR1 (adenosine deaminase, of 2ʹ-5ʹ oligoadenylates, which when polymerized ac- ti RNA-specific 1), NOS2 (nitric oxide synthase 2), OASs (2ʹ-5ʹ oligoadenylate vate the latent endoribonuclease RNase L to degrade synthases), RNase L, ISG20 (IFN-stimulated gene 20 kDa protein), PKR (IFN-induced, viral RNA transcripts. Lastly, the exonuclease ISG20 RNA-activated protein kinase) and ISG15. Finally, viperin and tetherin help to prevent (IFN-stimulated gene 20 kDa protein) degrades RNA viral assembly and release, respectively. Some of the effectors (such as MX proteins) transcripts belonging to VSV, influenza virus and appear to operate in both the nucleus and the cytosol (not shown). encephalomyocarditis virus . Some IFN-dependent enzymes edit viral RNAs and mouse MX2 are cytosolic proteins that target cyto- instead of degrading them. APOBEC3 (apolipo- plasmic viruses . Human MX1 exhibits the broadest protein B mRNA-editing enzyme, catalytic poly - range of antiviral activity, targeting all the infectious peptide 3) and ADAR1 (adenosine deaminase, genera of the Bunyaviridae family (that is, orthobunya- RNA-specific 1) are site-specific cytidine and adenosine viruses, hanta viruses, phleboviruses and nairoviruses) as deaminases, respectively. APOBEC3 converts cytidine to well as coxsackievirus and hepatitis B virus . This fits uridine in dsRNA, whereas ADAR1 catalyses the deami- 8,134 with its expression in human endothelial cells, hepa- to nation of adenosine to inosine . These incorporations cytes, plasma cytoid dendritic cells, peripheral bloo d lead to RNA destabilization and hypermutation after mononuclear cells and other myeloid cells. reverse transcription to cause lethal genome mutations in Current mechanistic models propose that GTPase- retroviruses such as HIV-1 (REF. 135). Different APOBEC driven MX protein oligomers form ring-like structures to isoforms (APOBEC3F and APOBEC3G) exhibit distinct 128,130 trap viral nucleocapsids and associated polymerases . mechanisms involving the processing of long terminal Such interactions may occur when MX proteins recog- repeats, and they may also interact with RNA and/or nize incoming viral ribonuclear particle complexes that the Gag protein from HIV-1 to prevent the packaging of 8,135 are destined for nuclear import or non-nuclear sites of these molecules into viral particles (FIG. 4). 378 | MAY 2012 | VOLUME 12 w w w.nature.com/reviews/immunol © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS Another IFN-inducible retroviral restriction factor The mature tetherin protein is a type II transmem- termed SAM-domain- and HD-domain-containing brane disulphide-linked dimer. Its C -terminal ecto- protein 1 (SAMHD1) was found more recently in domain is modified by a glycophosphatidylinositol 136–138 macrophages and dendritic cells , providing (GPI) linkage, and its N-terminal cytoplasmic domain some explanation as to why HIV -1 inefficiently trans- contains YxY motifs for binding the clathrin adaptor duces mononuclear phagocytes. SAMHD1 contains a proteins AP1 and AP2 during the endocytic internaliza - nucleotide-phosphohydrolase domain that hydrolyses tion of tethered virus for lysosomal delivery (TABLE 3). deoxynucleotides from the cellular poo (T l ABLE 3), and This topology may enable the association of tetherin depleting this nucleotide supply is currently posited to with lipid rafts and virion lipids so that it can be inco- r limit HIV -1 reverse transcriptase activity (FIG. 4). porated into HIV-1 particles. The secondary rather than Non-nucleotide targets are also subject to IFN- primary structure of tetherin is thought to dictate its mediated inhibition. The ubiquitin-like modifier ISG15 antiviral activity , with the N-terminal and coiled- restricts influenza viruses, herpesviruses, Sindbis virus, coil regions within the tetherin ectodomain minimally HIV-1, human papillomavirus (HPV) and Ebola virus required for viral retention (FIG. 4; TABLE 3). 139–141 in cells activated by type I IFNs , and many of these Viperin (also known as RSAD2) was originally –/– 139 viruses cause lethal infection in Isg15 mice . ISG15 shown to be induced by type I and II IFN signalling acts by conjugating target viral (and cellular) proteins in human cytomegalovirus-infected skin cells and in a process termed ISGylation . ISGylation substrates in mice infected with lymphocytic choriomeningi- include many newly synthesized viral proteins, such as tis virus . Viperin contains an S-adenosyl methio- the influenza A virus protein NS1 and the HPV capsid nine (SAM) domain and an N-terminal amphipathic proteins L1 and L2, which are needed for replication and helix that contributes to its antiviral activity by hel- p host evasion, and the HIV-1 protein Gag and the Ebola ing viperin to associate with ER membranes or lipid 151,152 virus protein VP40, which are involved in viral bud - droplets (FIG. 4; TABLE 3), where it interferes with 140,141 ding . ISGylation can interfere with modification of the assembly and egress of influenza virus and hepat-i these viral proteins by ubiquitin, which would otherwise tis C virus particles. This may occur through the dis- help to activate their functions . ruption of ER-derived lipid rafts that transport viral Nitrosylation is another post-translational modific-a envelope proteins to the plasma membrane, possibly tion that inhibits viruses. NO released by IFN-induced via the inhibition of farnesyl pyrophosphate synthase, NOS2 blocks DNA viruses — including poxviruses which is involved in cholesterol and isoprenoid sy- n 151,152 (such as ectromelia virus and vaccinia virus), herpes- thesis . Recent work also demonstrates that viperin viruses (such as HSV-1 and Epstein–Barr virus) and inhibits dengue virus, HIV-1 and West Nile virus, rhabdoviruses (such as VSV) — as well some RNA although whether it uses similar mechanisms remains 7,27,142–144 150,153 viruses (such as coxsackie B3 virus) . Where untested . examined, the loss of antiviral effector function in Numerous IFN-inducible restriction factors therefore –/– Nos2 mice coincided with heightened susceptibility target each stage of the viral life cycle in a variety of cell to viral infection (TABLE 2). The processes targeted by types, ensuring broad protective coverage to combat this NO include early and late viral protein synthesis, as welldi verse group of pathogens. as S-nitrosylation of structural proteins (in the case of VSV) or cysteine proteases (in the case of coxsackie B3 Conclusions and future directions virus). They also extend to DNA replication (in the case An avalanche of information has emerged over the last of vaccinia virus) and to RNA or DNA synthesis via the 15 years on the sensory apparatus and signalling ca- s inhibition of an immediate-early gene encoding the trans- cades that mobilize innate immunity in response to 27,142–144 6 activator Zta (in the case of Epstein–Barr virus) . infection . By contrast, little is known about the cell- Thus, replicative viral DNA and RNA, as well as viral autonomous effector mechanisms that confer steriliz- proteins, serve as direct targets for IFN-mediated ing immunity. How do we actually kill intracellular modification and inactivation. pathogens, or at least restrict their growth? Remarkably, such mechanisms seem to operate across most vertebrate Preventing viral assembly, budding and release. cells, an inheritance foretold by the defence repertoires 1,2 Following replication, viral DNA, RNA and stru -c of plants and lower organisms , but with the added fea- tural proteins are packaged into nascent virions for tures of expansive diversification and induction by IFNs 3,8 budding and release. At least two recently described in larger, long-lived chordates . IFN-induced proteins — tetherin and viperin — affect Recent applications of systems biology have begun late-stage export. to unearth new IFN-induced antiviral factors (such as Tetherin (also known as CD317 and BST2) is a viral IFITMs) , and genome-wide in silico identification cou- restriction factor that prevents the release of HIV-1 pled with traditional loss-o -f function approaches has particles from infected macrophages, where it also revealed proteins with novel antibacterial activities (such ISGylation 145,146 16 The attachment of the serves as a target for the HIV-1 protein Vpu . In as GBPs) . This list will continue to grow as we probe the ubiquitin-like modifier ISG15 to addition, it prevents the release of filovirus, arenavirus interface between vertebrate hosts and microbial patho- either pathogen or host protein 154,155 and herpesvirus particles in response to type I IFN or gens using large-scale unbiased methods , in some targets to regulate their IFNγ stimulation in macrophages and plasmacytoid cases with the assistance of government centres dedicated function rather than stimulate degradation. dendritic cells. to the systematic study of infection (see REF. 156). NATUR E R EVIEWS | IMMUNOLOGY VOLUME 12 | MAY 2012 | 379 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS As next-generation informatics takes hold, we are genes is more than the sum of their individual parts, one MicroRNAs 154–156 likely to find new IFN-inducible proteins with unique and of the founding doctrines of systems biology . Single-stranded RNA molecules of approximately perhaps unusual functions in host defence. For example, Other outstanding questions include the identity of 21–23 nucleotides in length such proteins could protect the nucleus from retroviral the membrane signals, signatures and structures that that are thought to regulate the insertion or bacterial factors ; defend gap junctions allow the recruitment of effectors to intact or damaged expression of other genes. 158,159 from bacterial cell- to-cell spread ; alter microbial or pathogen compartments for their eventual removal, a host cell metabolism ; participate in pathogen-selective topic in which the IFN-inducible IRGs and GBPs will forms of autophagy ; or use different forms of nucleo- play a leading part. 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Proceedings of the National Academy of Sciences of the United States of America, 81 3

Publisher: Pubmed Central
Copyright: © Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2012
ISSN: 1474-1733
eISSN: 1474-1741
DOI: 10.1038/nri3210
Publisher site: See Article on Publisher Site

Abstract

REVIEWS Interferon-inducible effector mechanisms in cell-autonomous immunity John D. MacMicking Abstract | Interferons (IFNs) induce the expression of hundreds of genes as part of an elaborate antimicrobial programme designed to combat infection in all nucleated cells — a process termed cell-autonomous immunity. As described in this Review, recent genomic and subgenomic analyses have begun to assign functional properties to novel IFN-inducible effector proteins that restrict bacteria, protozoa and viruses in different subcellular compartments and at different stages of the pathogen life cycle. Several newly described host defence factors also participate in canonical oxidative and autophagic pathways by spatially coordinating their activities to enhance microbial killing. Together, these IFN-induced effector networks help to confer vertebrate host resistance to a vast and complex microbial world. Host effector mechanisms are essential for the survival examination of newly described ISGs reveals a highly Autophagy of all multicellular organisms. This is exemplified by di verse but integrated host defence programme dedicated A specialized process involving 13–16 cell-autonomous immunity in plants, worms, flies and to protecting the interior of a vertebrate cell . the degradative delivery of a portion of the cytoplasm or of mammals. In Arabidopsis spp., for example, a defin- When viewed on a microscopic scale, the cell int-e damaged organelles to the able set of resistance genes is mobilized during this rior represents an immense ‘subterranean landscape’ lysosome. Internalized programmed cell-intrinsic response to protect against to patrol and defend. A single human macrophage, for pathogens can also be diverse phytopathogens; this inherited response is example, occupies ~5,000 μm (REF. 17). Contrast this with eliminated by this pathway. 1,2 3 sometimes referred to as the ‘resistome’ . In higher spe- a mature HIV-1 particle (~200 nm ) or tubercle bacillus cies, however, the assembly of an antimicrobial arsenal (~5–10 μm ) and it quickly becomes apparent that most or resistome takes on multiple forms, because the bur - IFN-induced proteins will need to be dispatched to the 18,19 den posed by infection in these organisms is consider- site of pathogen replication to be effective . Likewise, able . Indeed, as many as 1,400 phylogenetically distinct the ability of compartmentalized pathogens to remain microorganisms can infect a single chordate host . largely sequestered in vesicles suggests that many IFN- To cope with this increased microbial challenge, vert-e induced effectors also need methods to detect these brates have evolved additional levels of cell-autonomousm embrane-bound sanctuaries to eliminate the resident 18–20 control beyond the pre-existing repertoire of constitutive pathogens . host defence factors. These additional factors include Several ISGs fulfil both criteria. Members of an emer- g hundreds of gene products that are transcribed in ing superfamily of GTPases with immune functions recog - response to signals originating from the interferon (IFN), nize specific host lipid molecules on the pathogen vacuole 21–23 tumour necrosis factor (TNF), interleukin-1 (IL-1) and to mark it for disruption or delivery to lysosomes . 5,6 Toll-like receptor (TLR) families. Many of the induced Other recently identified IFN-induced proteins detect Section of Microbial proteins confer direct microbicidal immunity in al l ubiquitylated bacteria in the cytosol or exposed glycans Pathogenesis, Boyer Centre 7–9 25 nucleated cells . on host membranes that have been damaged by bacteria , for Molecular Medicine, IFNs are among the most potent vertebrate-derived and these markers stimulate the removal of the infecting 295 Congress Avenue, Yale University School of signals for mobilizing antimicrobial effector functions organism through autophagy. In addition, new antiviral Medicine, New Haven, 8,10,11 against intracellular pathogens . Nearly 2,000 human factors distinguish the cell ular entry, replication and exit Connecticut 06510, USA. 13,15 and mouse IFN-stimulated genes (ISGs) have been iden- points of HIV-1 and influenza A viruses . Less dis- e‑mail: tified to date, most of which remain uncharacterized (see criminating effector mechanisms are also deployed; for [email protected] 12 – doi:10.1038/nri3210 the Interferome database) (FIG. 1). The recent large-scale example, diatomic radical gases such as superoxide (O ) NATUR E R EVIEWS | IMMUNOLOGY VOLUME 12 | MAY 2012 | 367 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS and nitric oxide (NO) circumvent the need for recogni- a property first noted for NO against herpes simplex tion of the membranes surrounding sequestered bacte- virus, ectromelia virus and vaccinia virus . Both of these 7,26 ria and protozoa inside host cells . Because such gases strategies rely on an expanded family of oxidoreductases can diffuse large distances (several micrometres), they can and peroxidases that is now known to be present in also enter adjacent cells to confet r rans-acting immunity, essentially all phyl.a Arabidopsis Caenorhabditis Strongylocentrotus Drosophila Danio rerio Mus Homo sapiens thaliana elegans purpuratus melanogaster musculus sapiens Constitutive and inducible cell-autonomous defence IFN-inducible eﬀectors Type I Type III Type II IFN IFN IFN IFNGR1 IFNGR2 IFNAR1 IFNAR2 IL-10R2 IFNLR1 Cytoplasm JAK2 JAK2 TYK2 JAK1 TYK2 JAK1 P P P P GAF P P ISGF3 IRF9 Nucleus Type II IFN eﬀectors: Type I and type III IFN eﬀectors: DUOXs, NOXs, P ADAR, NOS2, Galectins, NRAMP1, APOBECs, PKR, GBPs, SQSTM1, GBPs, OASs, IDO, PKR, IRF9 IFITMs, SAMHD1, IFITMs, Tetherin, IRGs, Tetherin, IRGs, TRIMs, GAS ISRE ISG15, TRIMs, NDP52, Viperin NOS2, MXs, Viperin Antibacterial, antiprotozoal and Antiviral and antibacterial antiviral host defence programmes host defence programmes Figure 1 | Evolution of IFN-induced cell-autonomous host defence. a | The evolution of cell-autonomous immunity Nature Reviews | Immunology and the emergence of interferon (IFN)-induced effector mechanisms around the protochordate – vertebrate split (~530 million years ago). b | Cell-autonomous host defence proteins are canonically induced by IFNs via three receptor complexes −1 8 with high affinities for their ligands (K < 10 nM ) . The first receptor complex is a tetramer — composed of two chains of IFNγ receptor 1 (IFNGR1) and two chains of IFNGR2 — that engages type II IFN (that is, IFN γ) dimers. The second is a heterodimer of IFNα/β receptor 1 (IFNAR1) and IFNAR2 that binds to the type I IFNs: a family consisting of 13 different IFN α subtypes and one IFNβ subtype in humans. In the third receptor complex, interleukin-10 receptor 2 (IL-10R2) associates with IFNλ receptor 1 (IFNLR1; also known as IL-28Rα) to bind to three different type III IFN (that is, IFNλ) ligands (see REF. 8). Following receptor–ligand engagement, signals are transduced through signal transducer and activator of transcription 1 (STAT1) homodimers in response to IFNγ or through STAT1–STAT2 heterodimers in response to type I IFNs or IFN λ. Following their recruitment to the receptor complexes, these STAT molecules are phosphorylated by receptor-bound tyrosine kinases (namely, Janus kinases (JAKs) and tyrosine kinase 2 (TYK2)). Phosphorylated STAT1 homodimers (also known as GAF) translocate to the nucleus to bind to IFNγ-activated site (GAS) promoter elements to promote the IFN-induced expression of antimicrobial effector genes, some of which also require transactivation by IFN-regulatory factor 1 (IRF1) and IRF8. In the case of type I and III IFN signalling, phosphorylated STAT1–STAT2 dimers form a complex with IRF9 to yield IFN-stimulated gene factor 3 (ISGF3); this complex also translocates to the nucleus, where it binds to IFN-stimulated response elements (ISREs) in the promoters of different or overlapping IFN-stimulated effector genes. 368 | MAY 2012 | VOLUME 12 w w w.nature.com/reviews/immunol © 2012 Macmillan Publishers Limited. All rights reserved STAT1 STAT1 STAT1 JAK1 JAK1 STAT1 STAT1 STAT1 STAT1 STAT1 STAT2 STAT2 STAT2 REVIEWS It is the purpose of this Review to provide a broad bacteria . In mammals, three classes of cytokine- conceptual framework for understanding IFN-induced inducible oxidoreductases control ROS and RNS pro - cell-autonomous host defence and to highlight the grow - duction. NADPH oxidases (NOXs) directly catalyse the ing list of effectors that combat internalized bacteria, production of O , whereas dual oxidases (DUOXs) protozoa and viruses at the level of the infected mamma - produce H O (TABLE 1; Supplementary information 2 2 Reactive oxygen species lian cell. It focuses principally on the downstream killingS1 (figure)). In addition, nitric oxide synthases (NOSs) (ROS). Aerobic organisms derive their energy from the mechanisms, rather than on the well-known upstream synthesize NO, and the immunologically inducible reduction of oxygen. The microbial recognition and signalling events that elicit isoform NOS2 (also known as iNOS) synthesizes large metabolism of oxygen, and in IFN production. amounts of NO under infectious conditions. All three particular its reduction through classes of oxidoreductases may act simultaneously, the mitochondrial Cell-autonomous defence against bacteria sometimes even within the same host cell, depending electron-transport chain, generates by-products such as Bacteria infect host cells either through active inva - on the physiological setting and the activating stim - superoxide (O ) and 7,28 sion or via engulfment by professional phagocytes. uli . Non-enzymatic sources of ROS and RNS can downstream intermediates such Following their uptake, some bacterial species — such also contribute to host defence. For example, O can as hydrogen peroxide (H O ) 2 2 · as Mycobacterium tuberculosis and Salmonella enterica originate from mitochondrial leakage and NO can be and hydroxyl radicals ( OH). These three species are referred serovars — inhabit membrane-bound compartments generated by the action of gastric acid on NO that to as ROS. ROS can damage termed phagosomes, which they modify to limit is produced from dietary nitrates (NO ) by the oral important intracellular targets, 20 7,28,31,32 their exposure to microbicidal factors . By contrast, microbiota . such as DNA, lipids or proteins. Chlamydia spp. reside in reticulate structures called The NOX family of enzymes (NOX1 to NOX5) are inclusion bodies, which intercept Golgi-derived exo - the major ROS producers during infection . NOX2 Reactive nitrogen species (RNS). Nitric oxide (NO) cytic traffic as a source of nutrition . Other bacterial (also known as phagocyte oxidase) is responsible for the chemistry is complex because species, including Listeria and Shigella spp., escape respiratory burst in neutrophils, monocytes, macrophages of the extreme reactivity of their vacuoles to replicate in the cytosol. In each su- b and eosinophils. Genetic evidence underscores its impor - NO, which can result in the cellular locale, IFN-induced effector mechanisms are tance for host defence; indeed, congenital mutations in formation of different reactive nitrogen intermediates (RNI) mobilized to defend the interior of the host cell against genes encoding NOX2 subunits give rise to a collec - depending on the amount of bacterial infection. These mechanisms rely on oxida - tive syndrome termed chronic granulomatous disease. NO that is produced by cells. tive, nitrosative and protonative chemistries, as well Affected individuals suffer from recurrent infections with At low concentrations, NO as nutriprive (nutrient-restrictive) and membranolytic catalase-positive organisms such as Staphylococcus aureus, reacts directly with metals and activities. Serratia marcescens, Burkholderia cepacia, non-typhoidal other radicals. At higher 28,33 concentrations, indirect effects Salmonella spp. and M. tuberculosis (TABLE 2). prevail, and these include IFN-induced oxidative and nitrosative defence. NOX2 is a multisubunit enzyme comprising a trans- several oxidation or Cytotoxic gases are one of the most ancient and impor- membrane heterodimer — composed of gp91phox (also nitrosylation reactions with tant forms of cell-autonomous defence. These gases known as CYBB) and p22phox (also known as CYBA) oxygen that result in the production of various — collectively termed reactiv e oxygen species (ROS) — and three cytosolic subunits, namely p67phox (also congeners. NO and related RNI and reactive nitrogen species (RNS) — are generated by known as NCF2), p47phox (also known as NCF1) and are effective antimicrobial oxido reductases to confer microbicidal activity and p40phox (also known as NCF4). The cytosolic subunits agents and signal-transducing 7,26,28,30 regulate intracellular signalling . The targets of have SH3 domains that mediate intersubunit contacts molecules. ROS and RNS include bacterial DNA (which is dam - and PX domains for binding membrane lipids once Phagolysosomes aged via guanine base oxidation), lipids (which are they translocate to the gp91phox–p22phox complexes Intracellular vesicles that result damaged via peroxidation), and haem groups or iron– at the plasma membrane or on plasma membrane- from the fusion of phagosomes, 7,26 28 sulphur clusters within bacterial enzymes . Much of derived phagosomes (TABLE 1; Supplementary infor- which enclose extracellular the redox damage caused by these gases can be traced mation S1 (figure)). The assembly and activation of material that has been ingested, with lysosomes, to derivatives of O and NO. For example, the sequen- NOX2 holoenzymes also requires several GTPases. which contain lytic enzymes tial addition of single electrons to O yields hydrogen RAC1 and RAC2 facilitate this process under basal and antimicrobial peptides. peroxide (H O ) and then the hydroxyl radical (OH), conditions , whereas the recently described GTPase 2 2 both of which are more powerful oxidants than their guanylate-binding protein 7 (GBP7) operates after NADPH oxidases 26 – 16 pre decessor . Likewise, the reaction of NO with O , IFNγ stimulation . IFNγ-induced GBP7 specifi- Enzyme systems that consist of multiple cytosolic and other ROS or thiols yields intermediates with potent cally recruits cytosolic p67phox–p47phox heter-o membrane-bound subunits. bactericidal properties: dinitrogen oxides (N O and dimers to gp91phox–p22phox complexes on bacterial 2 3 The complex is assembled in N O ), compound peroxides (ONOO ) and nitroso- phagosomes containing Listeria monocytogenes or 2 4 activated phagocytic cells on 7,26 16 thiol adducts (RSNO) . Within phagolysosomes, Mycobacterium bovis bacillus Calmette–Guérin (BCG) the plasma and phagosomal membranes. NADPH oxidase O undergoes spontaneous dismutation to H O , and (FIG. 2). The proximity of phagosomal NOX2 to intra- 2 2 2 uses electrons from NADPH to stable nitrogenous end products such as nitrite (NO ) luminal bacteria may heighten IFN-induced killing, as reduce molecular oxygen to are converted back at low pH to the volatile NO gas; subsequent fusion with lysosomes favours dismutation form superoxide anions. 7,9 – both mechanisms aid bacterial killing . of O to the more-damaging oxidant H O (REF. 9). In Superoxide anions are 2 2 2 Given the toxicity of these molecules, it is not sur - addition to GBP7, the IFNγ-activated GTPase leucine- enzymatically converted to hydrogen peroxide, which in prising that the production of ROS and RNS is tightly rich repeat kinase 2 (LRRK2) has recently been reported neutrophils can undergo 34 controlled and often compartmentalized to limit to promote NOX2 activity against S. Typhimurium . further conversion by self-injury. This has the added benefit of maximiz- How LRRK2 exerts its effects and whether it works myeloperoxidase to ing microbicidal activity when production is loca-l in tandem with GBP7 on phagosomal membranes is hypochloric acid, a highly toxic and microbicidal agent. ized to phagosomes and phagolysosomes that contain currently unknown. NATUR E R EVIEWS | IMMUNOLOGY VOLUME 12 | MAY 2012 | 369 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS Other IFNγ-induced enzymes provide oxidative such mechanisms operate during vertebrate immu- Respiratory burst defence in non-phagocytic cells, such as epithelial cells nity in vivo . Thus, IFN-inducible NOXs and DUOXs The process by which molecular oxygen is reduced lining the airways, oral cavity and gastrointestinal tract. restrict bacterial colonization not only of immune cells by the NADPH oxidase system The IFNγ-inducible enzymes NOX1 and DUOX2 but also of stromal cells. to produce reactive oxygen – 28 generate O and H O , respectively, in these cells NOS2 is expressed in a variety of immune and non- 2 2 2 species. (Supplementary information S1 (figure)). At the plasma immune cell types following stimulation by type I IFNs membrane, H O can form hypothiocyanite (OSCN ), (that is, IFNα and IFNβ) and by IFNγ. Signals from Chronic granulomatous 2 2 disease which acts as a potent chemorepellent against bacte - otTM her cytokines (notably, TNF, lymphotoxin-α and TM An inherited disorder caused 35–37 HB HB FAD NADPH rial invasion and killL s isteria and Salmonella spp. . IL-1β) anHB d from microbHB ial proFA duDcts NADPH (such as lipopol-y TM TM by defective oxidase activity in Indeed, recent reports show that impaired clearance of saccharides and lipopeptides) also synergize with IFNs HB HB FAD NADPH HB HB FAD NADPH the respiratory burst of 7,39 Salmonella spp. follows the silencing of DUOX expre -s for NOS2 induction . To date, most work has focused phagocytes. It results from PX PR SH3 PB1 SH3 PX PR SH3 PB1 SH3 mutations in any of five genes sion in zebrafish intestinal epithelium, indicating that on NOS2 activities in mouse macrophages, as human TM that are necessary to generate PX SH3 SH3 AIR PR PX PX PR PR SH3 SH3 PB1 PB1 SH3 SH3 PX SH3 SH3 AIR PR HB HB FAD NADPH the superoxide radicals TM TM TM TM TM PX PX SH3 SH3 SH3 PC AIR PR PX SH3 SH3 AIR PR required for normal phagocyte TM PX SH3 PC HB HB FAD NADPH HB HB FAD NADPH HB HB HB HB FA FAD D NADPH NADPH HB HB FAD NADPH function. Affected patients HB HB FAD NADPH Table 1 | IFN-induced effector molecules that combat intr TMacellular bacteria and parasites PX PX SH3 SH3 PC PC PX PR PB1 SH3 PX PX PR PRSH3 PB1PB1 SH3SH3 suffer from increased HB HB FAD NADPH IFN-induced effector Member or subunit Domain structure susceptibility to recurrent PX PX SH3 PR SH3 PB1 PRSH3 TM TM TM PX PX SH3 PR SH3 PB1 AIRSH3 PR PX SH3 SH3 PR PX PX PR PR SH3 SH3 PB1 PB1 SH3 SH3 PX PX PR PR SH3 SH3 PB1 PB1 SH3 SH3 PX PR SH3 PB1 SH3 infections. TM PX PR SH3 PB1 SH3 NOX family gp91phox HB HB HB HB HB HB FA FA FAD D D NADPH NADPH NADPH TM TM TM TM TM TM PX SH3 SH3 PR PX HB SH3 SH3 HB PR FAD NADPH PX SH3 PC PX PX PX PRSH3 SH3SH3 SH3 SH3 PB1 AIR AIR PR PRSH3 PX SH3 SH3 AIR PR PX PX HB SH3 SH3 SH3 SH3 HB AIR AIR FAD PR PR NADPH HB HB HB HB FA FAD D NADPH NADPH HB HB HB HB HB HB FA FA FAD D D NADPH NADPH NADPH PX SH3 SH3 AIR PR PerD EF HB HB FAD NADPH PerD EF HB HB FAD NADPH PX PR PB1 SH3 p22phox PX PX PX SH3 SH3 SH3 SH3 PC PC AIR PR PX PX SH3 SH3 PC PC PX SH3 PC PX PX PRSH3SH3 PCPB1 SH3 PX PX PR PR SH3 SH3 PB1 PB1 SH3 SH3 PerD EF HB HB FAD NADPH PPerD erD PX EF EF PR SH3HB HB PB1 HB HBSH3 FA FAD D NADPH NADPH PerD EF HB HB FAD NADPH PX PX PX PRSH3 SH3 SH3 SH3 PCPB1PR SH3 p67phox PX PX PR PR PB1 PB1 SH3 SH3 PX PX PX PX PX PR PR PR PR PRSH3 SH3 SH3 SH3 PB1PB1 PB1 PB1 PB1 SH3SH3 SH3 SH3 SH3 PX PX PR PRSH3 PB1PB1 SH3SH3 PX PR PB1 SH3 PX SH3 SH3 AIR PR PX PX SH3 SH3 SH3 SH3 AIR AIR PR PR PX PR PB1 SH3 PerD EF HB HB FAD NADPH PerD PX EF SH3 HBSH3 AIR HB PR FAD NADPH PX SH3 SH3 AIR PR PX SH3 SH3 PR p47phox PX PX PX PX PX SH3 SH3 SH3 SH3 PR SH3 SH3 SH3 SH3 PB1 AIR AIR AIR PRSH3 PR PR PR PX PX PX PX SH3 SH3 SH3 SH3 SH3 SH3 SH3 SH3 AIR AIR PR PR PR PR PX SH3 SH3 PR PX SH3 PC PX PX PX SH3 SH3 SH3 SH3 PC PC PR PX SH3 PC PerD EF HB HB FAD NADPH PX SH3 PC PX SH3 SH3 PR p40phox PX PX PX PX SH3 SH3 SH3 SH3 PC PC PC PC PX SH3 PC PX PX PX PR PR PR PB1 PB1 PB1 SH3 SH3 SH3 PerD PX EF PR HB PB1 SH3 HB FAD NADPH PPerD erD EF EF HB HB HB HB FA FAD D NADPH NADPH PerD EF HB HB FAD NADPH PerD EF HB HB FAD NADPH PerD PX EF PR HB PB1 SH3 HB FAD NADPH NOXA1 HB PX PXBH CaM PR PR FMN/F PB1 PB1 ADSH3 SH3 NADPH HB PX PX PXBH CaM PR PR PR FMN/F PB1 PB1 PB1 ADSH3 SH3 SH3 NADPH PerD EF4 HB HB FAD NADPH PX PX SH3 SH3 SH3 SH3 PR PR PX SH3 SH3 PR PX SH3 SH3 PR PPPerD erD erD EF EF EF HB HB HB HB HB HB FA FA FAD D D NADPH NADPH NADPH PerD EF HB HB FAD NADPH PerD PX EF SH3 HBSH3 PR HB FAD NADPH PerD HB PXBH EF SH3 CaM HBSH3 FMN/FAD PR HB NADPH FAD NADPH NOXO1 HB PX PX PX PXBH SH3 SH3 SH3 SH3 CaM SH3 SH3 SH3 SH3 FMN/FAD PR PR PR PR NADPH PerD EF4 HB HB FAD NADPH PerD EF HB HB FAD NADPH GD DUOX family DUOX1 PPPerD erD erD GDEF EF EF HB HB HB HB HB HB FA FA FAD D D NADPH NADPH NADPH PerD EF HB HB FAD NADPH PerD EF HB HB FAD NADPH PPerD erD EF EF HB HB HB HB FA FAD D NADPH NADPH PPPerD erD erD GDEF EF EF CTHD HB HB HB HB HB HB FA FA FAD D D NADPH NADPH NADPH GD GD GD CTHD DUOX2 HB BH CaM FMN/FAD NADPH PPPerD erD erD EF EF EF HB HB HB HB HB HB FA FA FAD D D NADPH NADPH NADPH PerD EF HB HB FAD NADPH PerD EF HB HB FAD NADPH M GD CTHD PPerD erD EF EF HB HB HB HB FA FAD D NADPH NADPH M PPPerD erD erD GD GD GDEF EF EF CTHD CTHD CTHD HB HB HB HB HB HB FA FA FAD D D NADPH NADPH NADPH DUOXA1 or DUOXA2 HB HB BH BH CaM CaM FMN/F FMN/FAD AD NADPH NADPH HB BH CaM FMN/FAD NADPH HB BH44 CaM FMN/FAD NADPH HB BH4 CaM FMN/FAD NADPH HB BH CaM FMN/FAD NADPH M GD CTHD M GD CTHD GD NOS family NOS2 HB BH CaM FMN/FAD NADPH GD CTHD P GD CTHD P GD CTHD IRG family Human IRGM (a to e isoforms)* GD GD GD GD GD HB HB HB GDBH BH BH CaM CaM CaM ∆CTHDFMN/F FMN/F FMN/FAD AD AD NADPH NADPH NADPH GD GD CTHD P GD GD 444 ∆CTHD CTHD P M HB GDBH CaMCTHD FMN/FAD NADPH HB GD GDBH CaMCTHD CTHD FMN/FAD NADPH Mouse IRGM1 to IRGM3 GD GD CTHD CTHD HB HB GD GDBH BH4 CaM CaMCTHD FMN/F FMN/FAD AD NADPH NADPH HB HB HB BH BH BH CaM CaM CaM FMN/F FMN/F FMN/FAD AD AD NADPH NADPH NADPH GD 444 CTHD GD ∆CTHD GD ∆CTHD TM TM M GD CTHD M GD CTHD M M GD GD GD CTHD CTHD CTHD IRGA, IRGB, IRGC or IRGD M GD CTHD M GD CTHD GD GD GD groups GD CTHD P TM TM M GD GD CTHD GD GD GD GD GD GD GD CTHD GD GD CTHD CTHD GBP family Human GBP1 to GBP6 and GD ∆CTHD GD GD GD CTHD CTHD CTHD PP GD CTHD P GD CTHD P GD CTHD P GD CTHD mouse GBP1 to GBP11 GD GD GD GD GD CTHD CTHD CTHD CTHD CTHD P GD CTHD M M M GD GD GD CTHD CTHD CTHD OR HB OR HB M GD GD ∆CTHD CTHD GD ∆CTHD GD GD GD ∆CTHD ∆CTHD CTHD P TM GD ∆CTHD M GD CTHD M M GD GD CTHD CTHD M M M GD GD GD GD ∆CTHD CTHD CTHD CTHD Human GBP3ΔC OR OR HB HB GD ∆CTHD TM TM TM TM NRAMP family NRAMP1 TM GD GD GD CTHD CTHD CTHD PPP TM GD CTHD P CRD1 CRD2 CRD1 GD CRD2 CTHD P GD GD GD CTHD CTHD CTHD PPP TM GD GD CTHD CTHD PP GD GD GD ∆CTHD ∆CTHD ∆CTHD GD ∆CTHD IDO family IDO1 or IDO2 CRD1 CRD2 OR HB NLDCRD1 CRD2 CRD2 GD ∆CTHD NLD GD GD ∆CTHD ∆CTHD CRD2 GD GD GD ∆CTHD ∆CTHD ∆CTHD TM TM TM Galectin family Galectin 3 NLD CRD2 TM NLDCRD1 CRD2 CRD2 OR OR HB HB OR HB CRD1 CRD2 OR OR HB HB TM TM TM TM TM OR HB TM Galectin 8 or galectin 9 CRD1 CRD2 CRD1 CRD2 OR HB CRD1 CRD2 LIR LIR Ubiquitin-binding SQSTM1 NLDCRD1 CRD2 CRD2 CRD1 CRD1 CRD2 CRD2 CRD1 CRD2 PB1 CRD1ZZ CRD2 OR UBA HB ‡ OR OR HB HB PB1 ZZ UBA CRD1 CRD2 receptors LIR LIROR HB OR HB OR OR OR HB HB HB NLDCRD1 CRD1 CRD2 CRD2 CRD2 OR OR HB HB NLD CRD2 NLD NLD CRD2 CRD2 LIZ NLD PB1 PB1 ZZ ZZ CRD2UBA UBA NDP52 LIZ NLD CRD2 CC UBA CC UBA NLDCRD1 CRD2 CRD2 CRD1 CRD2 CRD1 CRD1 CRD2 CRD2 LIZ LIZ CRD1 CRD2 CRD1 CRD1 CRD1 CRD2 CRD2 CRD2 CRD1 CRD2 AIR, autoinhibitory region; BH, tetrahydrobiopterin-binding domain; CaM, calmodulin-binding domain; CC, coiled-coil; CTHD, CRD1 CRD2 LIR CC UBA CC UBA CRD1 CRD2 CRD1 CRD1 CRD1 CRD2 CRD2 CRD2 CRD1 CRD1 CRD1 CRD2 CRD2 CRD2 C-terminal helical domain; CRD, carbohydrate-recognition domain; DUOX, dual oxidase; EF, EF hand domain; FAD, flavin adenine PB1 ZZ UBA NLD NLD NLD CRD2 CRD2 CRD2 Nature Reviews Nature Reviews dinucleotide binding site; FMN/FAD, flavin mononucleotide or flavin adenine dinucleotide binding site; GBP, guanylate-binding NLD CRD2 LIR LIR LIR LIR LIR NLD CRD2 NLD CRD2 NLD NLD NLD NLD CRD2 CRD2 CRD2 CRD2 LIR protein; GD, GTPase domain; HB, haem-binding site; IDO, indoleamine 2,3 -dioxygenase; IFN, interferon; IRG, immunity-related LIZ PB1 PB1 CRD1 CRD1 CRD1ZZ ZZ CRD2 CRD2 CRD2UBA UBA PB1 ZZ UBA PB1 PB1 ZZ ZZ UBA UBA Natur Nature Re e Reviews views GTPase; LIR, LC3-interacting region; LIZ, LC3-interacting zipper; M, myristoylation site; NADPH, nicotinamide adenine PB1 CRD1ZZ CRD2 LIR UBA CC UBA CRD1 CRD2 CRD1 CRD2 CRD1 CRD1 CRD1 CRD1 CRD2 CRD2 CRD2 CRD2 dinucleotide phosphate binding site; NLD, non-lectin domain; NOS, nitric oxide synthase; NOX, NADPH oxidase; NRAMP, natural LIZ LIZPB1 ZZ UBA LIZ LIZ LIZ resistance-associated macrophage protein; OR, oxidoreductase domain; P, isoprenylation site; PB1, phox and Bem1 domain, LIZ CC CC UBA UBA CC UBA CC CC LIR UBA UBA LIR LIR PC, phox and Cdc domain; PerD, peroxidase domain; PR, proline-rich domain; PX, phox domain for phospholipid binding; CC UBA LIZ LIR Nature Reviews PB1 ZZ UBA RR, arginine-rich domain; SH3, SRC homology 3 domain; SQSTM1, sequestosome PB1 PB1 ZZ ZZ1; TM, transmembr LIR UBA UBA ane domain; UBA, ubiquitin- LIR LIR LIR LIR LIR CC UBA PB1 ZZ UBA associated domain; ZZ, zinc fingers. *Human IRGM is constitutively expressed but participates in IFN-induced cell-autonomous PB1 ZZ UBA PB1 PB1 PB1 ZZ ZZ ZZ UBA UBA UBA PB1 PB1 ZZ ZZ UBA UBA LIZ Natur Nature Re e Reviews views immunity. Denotes indirect effectors that function via autophagy (only LIZ LIZIFN-inducible receptors are shown). Nature Reviews Natur Nature Re e Reviews views Nature Reviews LIZ CC UBA LIZ CC CC UBA UBA LIZ LIZ LIZ LIZ LIZ CC UBA Nature Reviews CC UBA CC CC CC UBA UBA UBA CC CC UBA UBA 370 | MAY 2012 | VOLUME 12 w w w.nature.com/reviews/immunol Nature Reviews Natur Nature Re e Reviews views Nature Reviews Nature Reviews © 2012 Macmillan Publishers Limited. All rights reserved Natur Natur Nature Re e Re e Reviews views views Natur Nature Re e Reviews views REVIEWS Table 2 | Genetic deficiencies in IFN-induced effector genes and susceptibility to infection Host locus Deficiency Susceptibility to intracellular pathogens Refs Human CYBA (encoding Autosomal mutation; B. cepacia, G. bethesdensis, M. tuberculosis, S. aureus, 28,33 p22phox)* complete or partial S. marcescens, Salmonella spp. CYBB (encoding X-linked mutation; gp91phox)* complete or partial IRGM Autosomal mutation; AIEC, M. tuberculosis 66–69 polymorphic MX1 Autosomal mutation; HBV57, HCV, measles virus 128 polymorphic NOS2 Autosomal mutation; M. tuberculosis 164 polymorphic SLC11A1 (encoding Autosomal mutation; M. tuberculosis 83 NRAMP1) polymorphic Mouse Cybb (encoding X-linked mutation; A. baumannii, A. phagocytophila, G. bethesdensis, 28,40,41 gp91phox) complete H. pylori, L. monocytogenes, S. aureus, S. Typhimurium Gbp1 Autosomal mutation; L. monocytogenes, M. bovis BCG, S. Typhimurium 16 complete Gbp5 Autosomal mutation; L. monocytogenes complete Ifitm3 Autosomal mutation; Influenza A virus 13 complete Irgm1 Autosomal mutation; C. trachomatis, L. monocytogenes, L. pneumophila, 22,52,61, complete M. bovis BCG, M. tuberculosis, S. Typhimurium, T. gondii, 95,102 T. cruzi Irgm2 Autosomal mutation; C. psittaci 58 complete Irgm3 Autosomal mutation; C. trachomatis, T. gondii 56,99 complete Irga6 Autosomal mutation; T. gondii 101 complete Irgb10 Autosomal mutation; C. trachomatis, C. psittaci 56,58 partial Irgd Autosomal mutation; T. gondii 95 complete Isg15 Autosomal mutation; HSV-1, murine gammaherpesvirus 68, influenza A 139 complete virus, Sindbis virus Mx1 Autosomal mutation; Influenza A virus, influenza B virus, Thogoto virus 128 complete or polymorphic Nos2 Autosomal mutation; C. trachomatis, coxsackie B3 virus, ectromelia virus, 7,39,41,91, complete L. major, L. monocytogenes, M. tuberculosis, P. yoelli, 93,94,144 S. Typhimurium, T. cruzi, T. gondii Prkra (encoding PKR) Autosomal mutation; Vaccina virus, West Nile virus 8 complete Rnasel (encoding Autosomal mutation; B. anthracis, E. coli, HSV-1, vaccinia virus, West Nile 8,165 RNase L) or OAS loci complete virus Rsad2 (encoding Autosomal mutation; West Nile virus 153 viperin) complete Slc11a1 (encoding Autosomal C. jejuni, L. donovani, L. major, M. avium, M. bovis BCG, 83 NRAMP1) mutation; complete S. Typhimurium or polymorphic G169D (Nramp1 ) AIEC, adherent invasive Escherichia coli; GBP, guanylate-binding protein; HBV57, hepatitis B virus 57; HCV, hepatitis C virus; IFITM, IFN-inducible transmembrane protein; IRG, immunity-related GTPase; ISG15, IFN-stimulated gene 15 kDa protein; MX1, myxovirus resistance 1; NOS2, nitric oxide synthase 2; NRAMP1, natural resistance-associated macrophage protein 1; OAS, 2ʹ-5ʹ oligoadenylate synthase; PKR, IFN-induced, RNA-activated protein kinase.*Other NADPH oxidase components are also affected (p47phox, p67phox ‡ § and p40phox). C. J. Bradfield and J.D.M., unpublished observations. A. R. Shenoy and J.D.M., unpublished observations. NATUR E R EVIEWS | IMMUNOLOGY VOLUME 12 | MAY 2012 | 371 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS mononuclear phagocytes produce lower NO level. s IRGs were first shown to target phagosomes and Experiments using NOS2 inhibitors that are relatively direct lysosomal membrane traffic in IFNγ-activated selective for this NOS isoform have implicated a role macrophages infected with M. tuberculosis . It is now for NO and its derivatives in the early cell-autonomous known that IRGs also exert membrane regulatory func - immune response to intracellular bacteria . This role was tions on other bacterial compartments, and their action further delineated in mice and macrophages deficient for has also been observed in human and mouse fibroblasts 39,40,41 51–54 NOS2 and/or gp91phox . M. tuberculosis is sensitive and epithelial cells . IRGs promote cell-autonomous to NO-mediated killing but relatively resistant to O immunity to vacuolar bacteria as diverse as M. tubercu- and H O , in part owing to its expression of the H O - losis, M. bovis, S. Typhimurium, Chlamydia trachomatis, 2 2 2 2 detoxifying enzyme KatG . NO exhibits molar potencies Chlamydia psittaci, Legionella pneumophila and Crohn’s comparable to the current antibiotics used to treat tuber- disease-associated adherent invasive Escherichia coli 22,23,51–61 culosis, and the tuberculocidal activity of some new drugs (AIEC) . Individual IRGs confer pathogen- (such as bicyclic nitroimidazoles) has been attributed to specific immunity in vitro and in vivo, indicating that their release of NO . By contrast, L. monocytogenes is they have non-redundant functions during host defence sensitive to O and H O but less vulnerable to NO, and (TABLE 2). Such specificity probably arises from the host- 2 2 2 S. enterica serovars are inhibited by both classes of chemi- derived interacting partners and trafficking pathways 39,41 cals . Such differences reflect the metabolic pathways used by a given IRG and the type of intracellular niche 18,19,51 and microbial DNA repair processes targeted by ROS and occupied by a given bacterial species . RNS, as well as the detoxifying systems expressed by the Recent studies have contributed to a conceptual bacteria (see TABLE 2). They may also reflect compar- t framework for how IRGs orchestrate immunity to dif- 21,23,53,54,59,60,62,63 mentalization; for example, L. monocytogenes becomes ferent compartmentalized pathogens . This sensitive to NO when trapped inside phagosomes, model posits co operative interactions between IRG sub- owing to synergism with other bactericidal insults or classes, as well as with SNARE proteins and autophagic the heightened RNS concentrations that accumulate in effectors that may disrupt the pathogen-containing a confined volume . Therefore, phagosomal escape of compartment before lysosomal delivery (FIG. 2) . L. monocytogenes before NOS2 recruitment could pro- IRGs are divided into two groups — GKS-containing vide a survival benefit for the pathogen. For this reason, IRGs and GMS-containing IRGs — based on their vertebrates have evolved other IFN-induced mechanisms canonical (lysine-containing) and non-canonical to deal with bacterial escapees, as discussed below. (methionine-containing) G1 motifs within the con- 18,19,51 served amino-terminal catalytic GTPase domain Lysosomal killing: phagosome maturation and (TABLE 1). IRGs in the GMS-containing subclass (IRGM1, autophagy. Acidified lysosomes are inimical for the IRGM2 and IRGM3 in mice; IRGM in humans) appear growth of most bacteria. Here, a low pH (~4.5–5.0) — to be intrinsic regulators that control the activities of which is generated via the action of proton-pumping their respective effectors, which can also include other 21,23,53,54,59,60,62,63 vacuolar ATPases and maintained with the assistance IRGs . For example, IRGM3 in the endo- of antiporters such as sodium/hydrogen exchanger 1 plasmic reticulum (ER) helps to maintain membran- o (NHE1) — enhances the bactericidal activity of both lytic GKS-containing IRGs (such as IRGA6 and possibly 7,9 ROS and RNS . In addition, an abundance of lumi- IRGB10) in the ‘off ’ state by acting as a non-canonical 62,63 nal proteases, lipases, glycosidases and antimicrobial guanine nucleotide dissociation inhibitor (GDI) . peptides contributes to the sterilizing power of ly- s When released from IRGM3, IRGA6 and IRGB10 45,46 osomes . This has resulted in some bacterial patho - directly target Chlamydia-containing inclusion bodies gens (such as M. tuberculosis) evolving strategies to avoid or disrupt the trafficking of sphingomyelin-containing 55,56 these degradative organelles, whereas other bacteria exocytic vesicles to these organelles . Such disruption (such as L. monocytogenes) try to escape into the cytosol. probably results in autophagic engulfment of the path- o 53 –/– –/– Stimulation of the infected cell with IFNγ prevents both gen and explains the susceptibility of Irgm3 , Irga6 Galectins 18,22,44 –/– of these evasion strategies . and Irgb10 fibroblasts to infection with C. trachomatis Lectins that bind a wide variety 52,56,58 At least two newly described families of IFN-inducible or C. psittaci . of glycoproteins and glycolipids containing GTPases — the 21–47 kDa immunity-related GTPases IRGM1 and its smaller constitutive human orthologue, β-galactoside. They have (IRGs) and the 65–73 kDa GBPs — traffic to vacuolar IRGM, engage their effectors when targeting M. tubercu- extracellular and intracellular and cytosolic bacteria, where they assemble membrane losis, M. bovis, S. Typhimurium, AIEC or early L. mono- functions, including the complexes to facilitate bacterial transfer to lysosomes cytogenes phagosomes as part of the IFNγ -induced regulation of apoptosis, RAS 16,18,19,21–23 21–23,51,54,57,59,60 signalling, cell adhesion and or disruption of the pathogen compartment . response to these bacteria . The translocation angiogenesis. IFN-inducible GTPases function together with three of IRGM1 to mycobacterial phagosomes involves the rec - ubiquitin-binding receptors — sequestosome 1 (SQSTM1; ognition of specific host phosphoinositide lipids (namely, SNARE proteins also known as p62), NDP52 and optineurin — that detect phosphatidylinositol -3,4,5-trisphosphate and, to a lesser (Soluble N-ethylmaleimide- ubiquitylated structures on bacteria, as well as wit h extent, phosphatidylinositol -3,4-bisphosphate) on the sensitive factor attachment protein receptor proteins). galectins that detect glycans that are exposed during nascent phagocytic cup (FIG. 2). Once recruited, IRGM1 A class of proteins that is bacterial escape into the cytosol. These receptors recruit interacts with and may regulate the assembly activity required for membrane fusion the autophagic machinery that engulfs bacteria for lyso - or phosphorylation status of snapin, a SNARE adaptor events that occur in the course 24,25,47–50 somal delivery . The resultant (auto)lysosomes kill protein that recruits dynein motor complexes to traffic of vesicle trafficking and secretion. and degrade the entrapped cargo. phagosomes and endosomes along microtubules towards 372 | MAY 2012 | VOLUME 12 w w w.nature.com/reviews/immunol © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS a Compartmentalized bacteria b Escaped cytosolic bacteria Bacterium Cytosol Disrupted PtdIns(4,5)P PtdIns(3,4,5)P 2 3 bacterial vacuole Ubiquitin IRGM1 Bacterial phagosome or inclusion body GBP2 SQSTM1 GBP1 GBP1 SQSTM1 Disruption? GBP7 LC3 Polymerization ATG4B IRGM3 IRGA6 or P Optineurin NDP52 LC3 IRGB10 Exposed P TBK1 IRGM1 LC3 glycans IRGM Snapin Galectin 3 ATG5 Autophagophore or galectin 8 engulfment LC3B Autophagophore Mitochondrion Cu 2+ Fe 2+ Mn ATP7A DAG NRAMP1 NOX2 Nucleus OH GBP7 or LRRK2 H H O 2 2 NO NOX2 PKCδ IFN-induced gene transcription AMPs NOS2 Autophagolysosome Autophagolysosome Figure 2 | Cell-autonomous mechanisms used by IFN-induced proteins against intracellular bacteria. Interferon (IFN)-inducible proteins are required for host resistance to intracellular bacteria. a | Specific immunity-related GTPases (IRGs), guanylate-binding proteins (GBPs) and other GTPases translocate to compartmentalized bacteria in phagosomes or inclusion bodies. Here, different membrane regulatory complexes — IRGM1–snapin, GBP1–sequestosome Nature Reviews | Immunology 1 (SQSTM1) and GBP7–ATG4B — are assembled. These complexes initiate autophagic capture and SNARE-mediated fusion of the 16,21–23 19,52,53 bacterial compartments with lysosomes . In addition, IRGM3–IRGA6 (or IRGB10) mediate vacuole disruption , and GBP7 (and possibly leucine-rich repeat kinase 2 (LRRK2)) help to assemble NADPH oxidase 2 (NOX2) on bacterial phagosomes, which mediates bacterial killing. Using this pathway, these GTPases can also deliver antimicrobial peptides (AMPs) to the autophagolysosome and, in the case of human IRGM, may instigate mitochondrial fission before autophagy . Other IFN-inducible components, such as natural resistance-associated macrophage protein 1 (NRAMP1), help to exclude 2+ 2+ + Mn and Fe from the bacterial phagosome, while importing protons (H ) into this compartment. Nitric oxide synthase 2 (NOS2), which synthesizes NO, works in concert with NOX2, which produces reactive oxygen species such as superoxide (O ) and hydrogen peroxide (H O ), to produce compound intermediates like peroxynitrite (not shown) that are highly 2 2 2 bactericidal. b | An emerging signature for the recognition of some escaped bacteria in the cytosol is ubiquitylation (either single or multiple modifications with monoubiquitin and/or polyubiquitin chains) (see REF. 47). SQSTM1, NDP52 and optineurin bind to ubiquitylated bacteria to initiate innate immune signalling and to recruit the autophagic machinery via LC3 family members. In addition, GBP1 and GBP2 polymerize around cytosolic bacteria in a ubiquitin-independent process that may recruit specific antimicrobial partners, while galectin 3 and galectin 8 bind to exposed glycans on the bacteria and, in the case of galectin 8, recruit NDP52 and downstream autophagic effectors . SQSTM1 also activates a second antibacterial pathway involving diacylglycerol (DAG) and protein kinase Cδ (PKCδ) to induce NOX2 complex assembly. Dashed lines indicate possible routes and consequences. PtdIns(4,5)P , phosphatidylinositol-4,5-bisphosphate; PtdIns(3,4,5)P , phosphatidylinositol-3,4,5-trisphosphate; TBK1, TANK-binding kinase 1. 21,64 maturing autolysosomes . Likewise, different human membranolytic, fusogenic and fission events in an indi- IRGM splice isoforms bind to the core autophagy proteins vidual cell. This accounts in part for why deficiencies in ATG5 and LC3B as well as the inner mitochondrial mem - GMS-containing IRGs cause such pronounced infectious brane lipid cardiolipin to induce mitochondrial fission phenotypes compared with those of GKS-containing 59,65 18,20,52,56–58 and autophagy ; these functions of IRGM may under- IRGs (TABLE 2). It may also explain why human lie its protective response to mycobacterial, Salmonella IRGM polymorphisms share genetic linkages with suscep - 23,54,59,60,65,66 spp. and AIEC infections . Thus, a single tibility to tuberculosis and Crohn’s disease across so many 66–69 GMS-containing IRG can act as a hub for coordinating geographically diverse populations . NATUR E R EVIEWS | IMMUNOLOGY VOLUME 12 | MAY 2012 | 373 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS In contrast to the IFN-inducible IRGs, GBPs target for binding ubiquitin and an internal or N-terminal escaped bacteria in addition to those residing within region that interacts with LC3 autophagy proteins 16,70,71 vacuoles . Nucleotide-dependent self-assembly of for delivering bacterial cargo to autophagic vacuoles some but not all GBPs — in which G domain dimers (FIG. 2; TABLE 1). Galactin 3 and galactin 8 contain pair with the carboxy-terminal helical domain (CTHD) carbohydrate-recognition domains, and galectin 8 to form GBP tetramers — helps to partition GBPs binds to NDP52, which links the recognition of sugar 16,72,73 between the cytosol and endomembranes of the cell moieties on bacteria with the autophagic machinery (P. Kumar and J.D.M., unpublished observations) further downstream (FIG. 2; TABLE 1). (TABLE 1). A C-terminal CaaX motif used for isoprenyla - NDP52 also recruits the IκB kinase (IKK) family 16,72–74 tion also contributes to this membrane attachmen t . kinase TBK1 (TANK-binding kinase 1) to ubiquitin- These structural features — along with an ability to o- li coated bacteria via the adaptor proteins SINTBAD gomerize with other GBPs or even interact with GMS- (also known as TBKBP1) and/or NAP1 (also known containing IRGs — dictate which endomembranes as AZI2) . TBK1 in turn phosphorylates optineurin to 16,72–76 individual GBPs occupy and aid GBP targeting to increase its affinity for ubiquitin; in this way, NDP52 both vacuolar and cytosolic bacteria (as the latter may and optineurin may cooperate to protect against 24,47 retain remnants of damaged host membrane on the sur- infection . Furthermore, NDP52 and SQSTM1 use face of their capsular coat following escape from the va-c septin- and actin-dependent autophagic pathways to uole) (C. J. Bradfield, P. Kumar and J.D.M., unpublished target cytosolic Shigella spp. and the small percentage 48,49 observations). This translocation of GBPs to bacteria of S. Typhimurium that escape their vacuole . By promotes intracellular defence againsL t . monocytogenes, contrast, autophagic delivery of non-motile L. monocy- S. Typhimurium, Chlamydia spp. and Mycobacterium togenes mutants occurs via a different, as yet unspeci- 16,70,71 49,50 spp. in both macrophages and epithelial cells . The fied, route . Because SQSTM1 activates a second lack of such cell-autonomous defence probably contr- ib antibacterial pathway involving diacylglycerol to induce –/– –/– 82 utes to the susceptibility of Gbp1 and Gbp5 mice to the assembly of NOX2 complexes , parallels may be bacteria (TABLE 2). drawn with the GBPs, which induce both oxidative The recent identification of interacting partners for and autophagic pathways to confer cell-autonomous GBP1 and GBP7 has begun to reveal the molecular host defence. mechanisms used by some of these GTPases to promote bacterial killig n . GBP1 interacts with the ubiquitin- Competing for intracellular cations. Facultative and binding protein SQSTM1, which delivers ubiquitylated obligate intracellular bacteria often have stringent metal protein cargo to autolysosomes, resulting in the genera - cation requirements for growth inside mammalian host tion of antimicrobial peptides that kill engulfeM. d bovis cells, which serve as a rich natural source of these chem -i 16,77,78 and L. monocytogenes . GBP7 recruits the autophagy cal elements. As a result, IFN-induced mechanisms have protein ATG4B, which drives the extension of autophagic evolved to restrict the intraphagosomal and cytosolic 2+ 2+ 2+ membranes around bacteria within damaged bacterial availability of Mn , Fe and Zn , and to enhance the + + compartments and assembles NOX2 on these compart- transport of Cu into the phagosome, as Cu helps to 16 83–85 ments (FIG. 2). GBP5, by contrast, binds NLRP3 (NOD-, drive the formation of microbicidal ROS . Indeed, 2+ 2+ LRR- and pyrin domain-containing 3) to promote specific the activation of macrophages by IFNγ lowers Mn , Fe 2+ + inflammasome responses during the infection of IFNγ- and Zn concentrations by ~2–6-fold and increases Cu activated macrophages by Listeria or Salmonella spp., levels by ~5 -fold within mycobacterial phagosomes . whereas in non-phagocytic cells heterotypic inte a rctions Part of the reduction in metal cation concentrations 2+ 2+ between GBPs may help to target cytosolic escaped bac - depends on a proton-dependent Mn and Fe efflux teria to autolysosomes (A. R. Shenoy, C. J. Bradfield and pump called natural resistance-associated macrophage J.D.M., unpublished observations). Thus, GBPs act in protein 1 (NRAMP1; encoded by Slc11a1), which is 83,87 concert — both temporally and physically — to confer upregulated by IFNγ . NRAMP1 prevents ion seques- their antibacterial effects. Moreover, they integrate oxi- tration specifically by phagosomal pathogens and com - dative, lysosomal and possibly inflammasome-relat ed petes with bacterial ion transporters for access to these killing as part of their host defence activities. nutritional metals (FIG. 2). For example, the growth In addition to being targeted by GBPs, cytosolic of S. Typhimurium mutants that lack mntH (which bacteria have recently been shown to encounter a sec- encodes an NRAMP1 homologue with a high affinity 2+ 2+ ond line of cell-autonomous defence orchestrated by for Mn and Fe ) or sitABCD (which encodes a second 2+ SQSTM1, NDP52, optineurin and galectins in mac- Mn -binding transport system) is attenuated in IFNγ- 24,25,47–50 rophages and epithelial cells . The IFN-inducible activated macrophages from mice that express the wild- proteins SQSTM1 and NDP52, along with basally type NRAMP1 efflux pump, but not in macrophages expressed optineurin, recognize bacteria coated with from congenic mice with a non-functional NRAMP1 G169D ubiquitin, whereas IFN-regulated galectins detect the efflux pump (derived from a defective Nramp1 β-galactoside moiety of polysaccharide sugars (host allele). Similarly, infection of macrophages by an glycans and microbial carbohydrates) that become M. tuberculosis strain lacking Mramp (another bacte- 2+ exposed on damaged membranes when bacteria escape rial NRAMP1 homologue) leads to increased Mn and 25,79–81 2+ their phagosome to reach the cytosol . SQSTM1, Fe concentrations within the phagosome, and this may NDP52 and optineurin all possess a C -terminal domain reduce bacterial viability . 374 | MAY 2012 | VOLUME 12 w w w.nature.com/reviews/immunol © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS IFNγ stimulation also regulates other cation In sum, synergistic IFN-inducible effector mecha- transport mechanisms, for example by inducing the nisms are deployed in the cytosol and in diverse intra - relocation of the P-type ATPase Cu pump ATP7A cellular compartments to control bacterial infection. For to the phagosome, where it can transport Cu across example, IRGs, GBPs and recognition receptors help to the membrane to promote the generation of intra- direct vacuolar bacteria as well as ‘marked’ cytosolic luminal hydroxyl radicals. This again leads to bacteria to acidified autophagolysosomes. Low lyso - intra phagosomal killing of bacteria. IFNγ stimulation somal pH, in turn, accelerates the dismutation of O to 2+ – concomitantly increases the expression of the Fe the more powerful oxidant H O , converts NO back 2 2 2 exporter ferroportin 1 (also known as SLC40A1) at to the toxic radical NO and drives hydroxyl radicaf lor- the plasma membrane, while decreasing transferrin mation with the aid of imported Cu . Together, these 2+ receptor expression to limit Fe uptake; both mecha- IFN-regulated proteins help to maximize oxidative, nisms further restrict the growth of S. Typhimurium nitrosative, protonative and membranolytic damage to in macrophages . bacterial targets in the lysosome. Cell-autonomous defence against protozoa In vertebrates, many protozoa are obligate intracell- u Parasite lar pathogens that depend on the host cell for specific amino acids and metal ions. The nutritional and safety needs of different parasites often dictate the type of compartment they inhabit (reviewed in REF. 90). For example, the apicomplexan parasite Toxoplasma gondii (which causes human toxoplasmosis) occupies a non- fusogenic vacuole that excludes most host-derived pro - Parasitophorous teins, whereas the kinetoplastid parasites Trypanosoma vacuole cruzi (which is responsible for Chagas disease) and IRGB6 Leishmania spp. (which trigger cutaneous, mucocuta- l -tryptophan IDO IRGB10 IRGA6 neous and visceral leishmaniasis) reside in the cytosol and in modified lysosomes, respectivel y . These strat- IRGA6 IRGD N-formyl- egies operate effectively in resting cells by allowing kynurenine the parasites access to nutrients while helping them to avoid contact with many host microbicidal proteins. GBP1 However, once cells become stimulated with IFNs, new ATG5 GBP5 GBP2 host defence pathways are transcriptionally induced to Parasitophorous help limit parasite infection. disruption Autophagophore IRGM1 IRGM2 IRGM3 Parasiticidal activities. Previous studies have high- lighted the role of NOS2 -mediated killing in cell- 2+ Fe Necroptosis 2+ autonomous defence against a variety of protozoa Mn (reviewed in REF. 7). The parasiticidal effects of NO are most evident in IFNγ- activated macrophages infected NRAMP1 Nucleus with Leishmania major amastigotes or T. cruzi trypo- mastigotes and in human and mouse hepatocytes infected with Plasmodium falciparum and Plasmodium 91–93 yoelli sporozoites, respectively (FIG. 3). Furthermore, NO –/– IFN-induced Nos2 mice were highly susceptible to these patho - gene transcription 91–93 NOS2 gens (TABLE 2). In the case of less virulent type II T. gondii tachyzoites, IFN-inducible NOS2 plays a more Autophagolysosome limited part, functioning at later time points after the IFN-inducible GTPases have contained parasite growth Figure 3 | Cell-autonomous mechanisms used by IFN-induced proteins against during the early stages of infection . For virulent type I intracellular protozoa. Different intracellular strategies are used by interferon Nature Reviews | Immunology (IFN)-inducible proteins against protozoa. Nitric oxide synthase 2 (NOS2) exerts T. gondii strains, however, NOS2 is essential, because potent parasiticidal activity, while GKS-containing immunity-related GTPases (IRGs) these parasites have evolved mechanisms to escape IRG- appear to be directly involved in parasite vacuole disruption once they reach the mediated inhibition in IFNγ-activated macrophages . parisitophorous compartment. This proceeds via autophagy-independent trafficking Here, NO does not appear to eliminate virulent T. gondii after release from IRGM1–IRGM3 or ATG5 and is mediated by cooperative IRG but instead imposes static, non-lethal control. How 62,63,103 loading . Guanylate-binding proteins (GBPs) — specifically GBP1–GBP2 and NO inhibits Toxoplasma parasites, along with malaria, GBP1–GBP5 complexes — also traffic to the parasitophorous vacuole, with Leishmania and Trypanosoma parasites, remains incom- uncharacterized effects on parasite control . Natural resistance-associated 2+ pletely understood, but haem-containing compounds macrophage protein 1 (NRAMP1) is important for restricting the uptake of Mn and 2+ (such as haemozoin) and protozoal cysteine proteases Fe by this compartment, whereas indoleamine 2,3 -dioxygenase 1 (IDO1) and/or appear to be likely targets for S-nitrosylation, which can IDO2 limit amino acid acquisition via the depletion of l -tryptophan. Dashed lines indicate possible routes or consequences. inactivate these enzymes . NATUR E R EVIEWS | IMMUNOLOGY VOLUME 12 | MAY 2012 | 375 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS Targeting the parasitophorous vacuole. As in the case T. gondii, Leishmania spp. and Chlamydia spp. in humans of bacteria, IFN-inducible IRGs and GBPs defend is often superseded by the NOS2 pathway in other species the interior of the host cell against protozoa. IRGM1, (such as mice and rats), in which NOS2 may represent a 7,108,111 IRGM3 and IRGA6 promote IFNγ-induced control more robust front-line defence mechanism . (but not TNF- or CD40-dependent control) of avirulent Overall, the relative potencies of NOS2, IDOs, IRGs 96–101 T. gondii in macrophages and astrocytes . IRGM1 and GBPs against protozoa reflect not only the species- also contributes to macrophage trypanocidal activity specific pathways available in vertebrates but also the (TABLE 2). Inhibition of avirulent T. gondii appears to co-evolutionary adaptations used by different parasites rely on several IRGs, with IRGM proteins providing a to survive within vertebrate host cells. regulatory function by acting as GDIs that release GKS- containing IRGs to target the parasitophorous vacuole Cell-autonomous defence against viruses (FIG. 3). Recent studies invoke a hierarchical model in Viruses were the first reported targets of IFN-mediated which IRGB6 and possibly IRGB10 act as forerunners immunity, and they are the one taxonomic group that to IRGA6 and then IRGD during their loading onto the can infect all nucleated cells (reviewed in REF. 8). Less parasitophorous vacuole some 90 minutes after parasite complex than eukaryotic protozoa and considerably entry. The recruitment of these molecules is followed smaller than most bacteria in terms of size and genome by vesiculation, membrane disruption and sometimes content, viruses nonetheless represent a major challenge 62,63 necroptosis . What remains unknown are the struc- to the host owing to their high mutation rates (up to –8 tural and biochemical cues for targeting these molecules 10 mutations per base per generation), their diverse to the parasitophorous vacuole and whether membrane cell tropisms and their ability to co-opt the replication deformation is directly due to IRG activity or a result of machinery of the cell. For these reasons, IFN-inducible some intermediary protein. These are topics of future proteins operate in multiple cell types and at all s -uc investigation. cessive stages of the viral life cycle, including entr y, Other proteins assist the relocation of IRGs to the replication, capsid assembly and release. parasitophorous vacuole. For example, ATG5 facilitates the release and transit of IRGA6 from its bound state . Blocking viral entry and uncoating. At least two IFN- Heterotypic interactions between different GBPs have inducible protein families have recently been shown also recently been shown to underlie the vacuolar targ- et to interfere with viral entry and uncoating: the IFN- ing of GBPs (FIG. 3). Hence, multiple parasitophorous inducible transmembrane (IFITM) proteins and the vacuole-damaging mechanisms are likely to ensue as the tripartite motif (TRIM) proteins. IRGs and GBPs converge on this organelle. Because viru - IFITM1, IFITM2 and IFITM3 restrict the entry and lent T. gondii strains (but not avirulent strains) exclude endosomal fusion of influenza A virus and flaviviruses 76,104,105 IRGs and GBPs from the parasitophorous vacuole , (such as West Nile virus and dengue virus) in both it is likely that these IFN-inducible GTPases exert a IFNγ- and IFNα-treated human cells . Recent studies strong selective pressure via their membrane regula - also extend the antiviral profile of these three IFITMs tory activities. Such pressure appears to be specific for to include HIV -1, coronaviruses and the Marburg and 114–116 different protozoa, as GBP1 is not recruited to T. cruzi Ebola filoviruses . In the case of IFITM3, a C-terminal compartments . transmembrane region and S-palmitoylation contribute to its antiviral activity in membrane-bound compartments 115–119 Restricting nutrient acquisition. Nutriprive mechanisms such as late endosomes and lysosomes (TABLE 3). are particularly effective against parasites. NRAMP1 IFITM3 is thought to deny cytosolic access to influ - prevents ion assimilation by Leishmania spp. (L. major enza A virus by preventing viral genomes from leaving th e 83 119 and L. donovani) and indoleamine 2,3 -dioxygenases endocytic pathway (FIG. 4). (IDOs) hamper amino acid acquisition . IDO1 and TRIMs also serve as viral restriction factors, particularly IDO2 are both IFN-inducible, haem-containing oxi- against retroviruses such as HIV-1. In vertebrates, many doreductases that are responsible for the initial rate- TRIMs are induced by IFNs (primarily by type I IFNs) in limiting step of the kynurenine pathway, in which they macrophages, myeloid dendritic cells, peripheral blood degrade l-tryptophan to generate N-formylkynurenine lymphocytes and fibroblasts . TRIM-dependent antiviral (FIG. 3; TABLE 1). Removal of l-tryptophan restricts the activity relies on a shared N-terminal RING domain that growth of Leishmania spp. and T. gondii (as well as that functions as an E3 ligase and/or on a C-terminal SPRY 120,121 of C. psittaci, Francisella spp., Rickettsia spp., herpes domain that enables protein–protein interactions simplex virus 1 and hepatitis B virus) in IFNγ-activated (TABLE 3). TRIM5α can restrict HIV-1 entry by binding to macrophages, dendritic cells, fibroblasts, epithelial the retroviral capsid to accelerate its cytoplasmic uncoating cells, astrocytes, endothelial cells and mesenchymala nd, as demonstrated more recently, by activating innate 107–111 stem cells . IDOs also inhibit T. cruzi via the down- immune signalling through associations with the E2 stream l-kynurenine catabolites 3-hydroxykynurenine ubiquitin-conjugating enzyme complex UBC13–UEV1A and 3-hydroxyanthranilic acid, which are likely to be (also known as UBE2N–UBE2V1), which activates TGF β- 112 122,123 toxic for T. cruzi amastigotes and trypomastigotes . activated kinase 1 (TAK1) to induce immune genes . Furthermore, in vivo blockade of IDOs using 1-methyl- Which of these two mechanisms predominates is as yet tryptophan results in profound host susceptibility to unresolved. In addition, TRIM22 combats hepatitis B T. gondii . This host-protective role of IDOs against virus and encephalomyocarditis virus by interfering with 376 | MAY 2012 | VOLUME 12 w w w.nature.com/reviews/immunol © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS pre-genomic RNA synthesis and protease activity, whereas The myxoma resistance proteins (MXs) are also IFNβ-inducible TRIM79α restricts tick-borne encephalitis antiviral effector molecules involved at an early stage virus by mediating the lysosomal degradation of the viral in type I IFN- and IFNλ-induced host defence against RNA-dependent RNA polymerase NS5 (REFS 124–126). orthomyxoviruses (such as influenza and Thogoto TM 128 Furthermore, IFNα-inducible TRIM21 delivers incoming viruses), bunyaviruses, togaviruses and rhabdo viruses . TM CD225 CD225 TM IgG-bound adenovirus to the proteasome through its E3 Human and mouse MX1, as well as mouse MX2, CD225 CD225 TM 127 CD225 CD225 128,129 ubiquitin ligase activity . Thus, the number of different exhibit antiviral activity . Mouse MX1 localizes to CD225 CD225 CBD CD225 CD225 TM CD225 CD225 CBD effector mechanisms used by members of the TRIM family promyelocytic leukaemia (PML) nuclear bodies and CD225 CD225 CBD CD225 CD225 CD225 TM CD225 CBD continues to grow. restricts nuclear viruses, whereas both human MX1 CD225 CD225 R BB1 BB2 CC COS FN3 PRY SPRY CD225 TM CD225 CBD R BB1 BB2 CC COS FN3 PRY SPRY CD225 CD225 R BB1 BB2 CC COS FN3 PRY SPRY CD225 TM CD225 CBD TM R BB1 TM TMBB2 CC COS FN3 Table 3 | Repertoire of IFN-induced antiviral effectors R BB1 BB2 CC COS FN3 PRY SPRY R BB1 BB2 CC COS FN3 CD225 CD225 CD225 CD225 CD225 CD225 CD225 CD225 CD225 CD225 CBD R BB1 BB2 CC COS FN3 R BB1 BB2 CC PRY SPRY IFN-induced Name Domain structur R BB1 TMBB2 e CC COS FN3 PRY SPRY R BB1 BB2 CC COS FN3 R BB1 BB2 CC PRY SPRY TM TM CD225 CD225 CBD effector family CD225 TM TM CD225 CBD RCD225 CD225 CD225 BB1 BB2 CD225 CD225 CD225 CC CBD CBD PRY SPRY TM TM TM R R BB1 BB1 BB2 BB2 CC CC COS FN3 PRY SPRY TM COS FN3 R BB1 TM TM TMBB2 CC RCD225 CD225 BB1 BB2 CD225 CD225 CC PRY SPRY CD225 CD225 CD225 CD225 RCD225 CD225 BB1 BB2 CD225 CD225 CC CD225 TM TM CD225 IFITM family IFITM1, IFITM2 or IFITM3 CD225 CD225 CD225 CD225 R RCD225 CD225 CD225 BB1 BB1 BB2 BB2 CD225 CD225 CD225 CC CC COS CBDFN3 PRY SPRY R BB1 BB2 CC PHD BR R BB1 BB2 CC COS FN3 R BB1 BB2 CC PRY SPRY RCD225 CD225 BB1 BB2 CD225 CD225 CC CD225 CD225 CD225 CD225 CBD CBD PHD BR RCD225 CD225 BB1 BB2 CD225 CD225 CC CBD CBD CD225 CD225 CD225 CD225 CBD CBD CD225 CD225 CBD R BB1 BB2 CC COS PHD FN3 BR PRY SPRY R RCD225 BB1 BB1 BB2 BB2 CD225 CC CC COS CBDFN3 PRY SPRY R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 P PRY RY SPR SPRY Y RCD225 CD225 CD225 BB1 BB2 CD225 CD225 CD225 CC COS FILCBD CBD CBDNHL FN3 R R BB1 BB1 BB2 BB2 CC CC PRY SPRY R BB1 BB2 CC R BB1 BB2 CC PHD BR IFITM5 CD225 CD225 CD225 CD225 CBD CBD NHL R BB1 BB2 CC FIL COS NHL FN3 R R BB1 BB1 BB2 BB2 CC CC FIL R R BB1 BB1 BB2 BB2 CC CC COS COS COS FN3 FN3 FN3 PRY SPRY R R R R BB1 BB1 BB1 BB1 BB2 BB2 BB2 BB2 CC CC CC CC COS ARF FN3 PRY SPRY PHD BR R R BB1 BB1 BB2 BB2 CC CC FIL NHL R BB1 BB2 CC TRIM family Subfamily TRIM C-I R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 P PRY RY SPR SPRY Y R BB1 BB2 CC ARF R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 P PRY RY SPR SPRY Y R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 P PRY RY SPR SPRY Y R R BB1 BB1 BB2 BB2 CC CC COS FN3 P PRY RY SPR SPRY Y R R BB1 BB1 BB2 BB2 CC CC ARF PRY SPRY R R R R R BB1 BB1 BB1 BB1 BB1 BB2 BB2 BB2 BB2 BB2 CC CC CC CC CC COS PHD FN3 P P PRY RY RY SPR SPR SPRY Y Y PHD BR R R R R R BB1 BB1 BB1 BB1 BB1 BB2 BB2 BB2 BB2 BB2 CC CC CC CC CC COS COS COS COS FN3 FN3 FN3 FN3 P P PRY RY RY SPR SPR SPRY Y Y R BB1 BB2 CC FIL NHL R BB1 BB2 CC ARF R BB1 BB2 CC PHD Subfamily TRIM C-III R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 P PRY RY SPR SPRY Y R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 R BB1 BB2 CC PHD R R R BB1 BB1 BB1 BB2 BB2 BB2 CC CC CC COS COS FN3 FN3 R R RR BB1 BB1 BB1 BB2 BB2 BB2 BB2 CC CC CC CC COS PHD COS FN3 BR R R BB1 BB1 BB2 BB2 CC CC R R BB1 BB1 BB2 BB2 CC CC COS NHL FN3 PRY SPRY R BB1 BB2 CC COS FIL FN3 R R R R BB1 BB1 BB1 BB1 BB2 BB2 BB2 BB2 CC CC CC CC COS COS ARF FN3 FN3 R BB1 BB2 CC PHD R BB2 CC COS R R BB1 BB1 BB2 BB2 CC CC P PRY RY SPR SPRY Y Subfamily TRIM C-IV R R BB1 BB1 BB2 BB2 CC CC COS COS FN3 FN3 R R BB1 BB1 BB2 BB2 CC CC P PRY RY SPR SPRY Y R R RR BB1 BB1 BB1 BB2 BB2 BB2 BB2 CC CC CC CC PHD COS BR P PRY RY SPR SPRY Y R R BB1 BB1 BB2 BB2 CC CC PHD BR PRY SPRY R R R BB1 BB1 BB2 BB2 BB2 CC CC CC MA PHD PHD FILTHNHL BR BR R R BB1 BB1 BB2 BB2 CC CC PRY SPRY R BB1 BB2 CC ARF R R R R R BB1 BB1 BB1 BB1 BB1 BB2 BB2 BB2 BB2 BB2 CC CC CC CC CC PHD P P PRY RY RY SPR SPR SPRY Y Y R BB2 CC COS R BB2 CC MATH R R R BB1 BB1 BB1 BB2 BB2 BB2 CC CC CC P PRY RY SPR SPRY Y R BB1 BB2 CC Subfamily TRIM C-V R BB1 BB2 CC R BB1 BB2 CC R R R BB1 BB1 BB2 BB2 BB2 CC CC CC MA FILTHNHL R BB1 BB2 CC FIL NHL R R R R R BB1 BB1 BB1 BB1 BB1 BB2 BB2 BB2 BB2 BB2 CC CC CC CC CC ARF FIL FIL NHL NHL R BB1 BB2 CC PHD PHD BR R R RR BB1 BB1 BB2 BB2 BB2 BB2 CC CC CC CC COS R R BB1 BB1 BB2 BB2 CC CC R R BB1 BB2 BB2 CC CC MATH R R BB1 BB1 BB2 BB2 CC CC PHD PHD BR BR R BB1 BB2 CC R R R BB1 BB1 BB2 BB2 BB2 CC CC CC PHD PHD BR BR R BB1 BB2 CC Subfamily TRIM C-VI R BB1 BB2 CC PHD PHD BR BR R R R BB1 BB1 BB1 BB2 BB2 BB2 CC CC CC PHD ARF BR R R BB1 BB1 BB2 BB2 CC CC PHD ARF R R R BB1 BB1 BB2 BB2 BB2 CC CC CC PHD ARF ARF BR RR BB1 BB2 BB2 CC CC COS NHL R R R R R BB1 BB1 BB1 BB1 BB2 BB2 BB2 BB2 BB2 CC CC CC CC CC MA PHD PHD PHD FILTH BR BR BR R BB2 CC R BB1 BB2 CC PHD PHD FIL NHL NHL BR BR R R R BB1 BB1 BB1 BB2 BB2 BB2 CC CC CC FIL FIL NHL NHL R R BB1 BB1 BB2 BB2 CC CC FIL Subfamily TRIM C-VII R BB1 BB2 CC PHD FIL NHL NHL R R RR BB1 BB1 BB1 BB2 BB2 BB2 BB2 CC CC CC CC PHD COS FIL NHL R R R BB1 BB1 BB1 BB2 BB2 BB2 CC CC CC PHD PHD FIL R R R BB1 BB1 BB2 BB2 BB2 CIDCC CC CC MA ARF FILTHNHL R BB1 BB2 CC FIL FIL NHL NHL NHL R R BB1 BB1 BB2 BB2 CC CC FIL R BB2 CC DYN LZ R R BB1 BB1 BB2 BB2 CIDCC CC ARF ARF FIL NHL NHL R R BB1 BB1 BB2 BB2 CC CC FIL R R BB1 BB1 BB2 BB2 CC CC ARF ARF R BB2 CC COS RR BB1 BB2 BB2 CC CC ARF COS Subfamily TRIM C-IX R R RR R BB1 BB1 DYN BB2 BB2 BB2 BB2 BB2 CIDCC CC CC CC CC LZMA ARF ARF COS COS TH R BB1 BB2 CC PHD R BB1 BB2 CC ARF R R R R BB1 BB1 BB1 BB2 BB2 BB2 BB2 CC CC CC CC ARF ARF ARF DYN LZ CID R R BB1 BB1 BB2 BB2 CC CC PHD PHD R BB1 BB2 CC ARF R R R BB1 BB1 BB1 BB2 BB2 BB2 CC CC CC PHD PHD ARF DYN LZ R R R BB1 BB1 BB2 BB2 BB2 CC CC CC MA PHD PHD TH R BB1 BB2 CC PHD R R R BB2 BB2 BB2 CC CC CC MA MA MATH TH TH Subfamily TRIM C-X R RR BB1 BB2 BB2 BB2 CC CC CC PHD COS R R R BB1 BB1 BB1 BB2 BB2 BB2 CC CC CC PHD PHD PHD CID R R BB2 BB2 CC CC COS COS R R BB1 BB1 BB2 BB2 CC CC PHD PHD R DYN BB2 CC LZCOS R BB2 CC COS R OAS1 BB2 CC COS R R BB2 BB2 CC CC COS COS R BB2 CC RR BB2 BB2 CC CC COS Subfamily TRIM C-II R R RR R R BB2 BB2 BB2 BB2 BB2 BB2 CC CC CC CC CC CC MA COS COS COS TH CID OAS1 R DYN BB2 CC LZCOS R RR BB2 BB2 BB2 CC CC CC MA MA COS TH TH R OAS1 CC MATH R BB2 BB2 CC MATH OAS2.1 OAS2.2 R R BB2 BB2 CC CC MA MATH TH R BB2 CC MATH R OAS1 BB2 CIDCC MATH Subfamily TRIM C-VIII R BB2 CC MATH R R R BB2 BB2 BB2 CC CC CC MA MATH TH OAS2.1 OAS2.2 DYN LZ R R BB2 BB2 CC CC MA MATH TH R R OAS2.1 BB2 BB2OAS2.2 CC CC R R BB2 BB2 CC CC OAS3.1 OAS3.2 OAS3.3 R OAS1 BB2 CIDCC R R BB2 BB2 CID CIDCC CC OAS2.1 OAS2.2 CID Subfamily TRIM C-XI R BB2 CC R R R DYN BB2 BB2 BB2 CC CC CC LZ OAS3.1 DYN OAS3.2 OAS3.3 LZ DYN DYN LZ LZ R R OAS3.1 BB2 BB2OAS3.2 CC CC OAS3.3 OAS1 OAS2.1 OASL UBL OAS2.2 OAS3.1 OAS3.2 CID OAS3.3 MX family MX1 or MX2 OASL DYN UBL LZ CID CID OAS1 CID CID OASL UBL OAS2.1 OAS2.2 CID CID DYN DYN CID LZ LZ OAS3.1 OAS3.2 OAS3.3 DYN DYN CID LZ LZ CID OASL DYN DYN UBLCID CID LZ LZ DYN LZ OAS family OAS1 DYN LZ OAS1 DYN DYN DYN LZ LZ LZ OAS1 CID CID OAS2.1 OAS1 OAS1 OAS2.2 OAS3.1 OAS3.2 OAS3.3 DYN DYN LZ LZ RBM1 RBM2 S/T-kinase OASL UBL RBM1 OAS2.1RBM2 OAS2.2 S/T-kinase OAS2 OAS2.1 OAS2.1 OAS2.1 OAS2.2 OAS2.2 OAS2.2 OAS3.1 OAS3.2 OAS3.3 OAS1 RBM1 RBM2 S/T-kinase OASL UBL OAS1 RBM1 OAS1 RBM2 S/T-kinase OAS1 OAS1 OAS1 OAS1 OAS3.1 OAS1 OAS3.2 OAS3.3 OAS3 OAS3.1 OAS3.2 OAS3.3 OAS3.1 OAS3.1 OAS1 OAS3.2 OAS3.2 OAS3.3 OAS3.3 OAS2.1 OAS1 OAS1 OAS1 OASL UBL OAS2.2 ANK RBM1 RBM2 S/T-kinase OAS1 OAS2.1 OAS2.1 OAS1 OAS2.2 OAS2.2 OAS2.1 ANK OAS2.2 OAS2.1 OAS2.2 OAS2.1 OAS2.2 STYK PUG OAS2.1 OAS2.2 OAS2.1 OAS2.2 OASL ANK UBL OASL OAS2.1 UBL OAS2.2 OAS2.1 OAS2.1 OAS3.1 OASL OASL OASL UBL UBL OAS2.2 OAS2.2 OAS3.2 OAS3.3 OAS2.1 OAS2.2 STYK PUG RBM1 RBM2 S/T-kinase ANK OAS2.1 OAS2.2 OAS2.1 OAS3.1 OAS3.1 OAS2.2 STYK OAS3.2 OAS3.2PUGOAS3.3 OAS3.3 OAS3.1 OAS3.1 OAS3.2 OAS3.2 OAS3.3 OAS3.3 OAS3.1 OAS3.1 OAS3.2 OAS3.2 OAS3.3 OAS3.3 OAS3.1 OAS3.2 OAS3.3 STYK PUG PKR EIF2AK OAS3.1 OAS3.2 OAS3.3 RBM1 OAS3.1 OAS3.1 OAS3.1RBM2 OAS3.2 OAS3.2 OAS3.2 S/T-kinase OAS3.3 OAS3.3 OAS3.3 OASL ANK UBL OAS3.1 OAS3.1 OAS3.2 OAS3.2 OAS3.3 OAS3.3 UBL OASL OASL UBL OASL UBL OASL ZF1 UBL CD STYK PUG ZF2 CD OASL UBL OASL UBL RBM1 OASL RBM2 UBL S/T-kinase RBM1 RBM2 S/T-kinase RBM1 RBM1 OASL ANK RBM2 RBM2 UBL S/T S/T-kinase -kinase OASL UBL UBL RNase L RNAseL OASL OASL UBL ZF1 CD ZF2 CD UBL OASL OASL ZF1 UBL CD ZF2 CD STYK PUG ANK ZF1 CD ZF2 CD RBM1 RBM2 S/T-kinase STYK PUG RBM1 RBM2 S/T-kinase RBM1 SAM RBM2 HD S/T-kinase RBM1 RBM2 S/T-kinase APOBEC3 APOBEC3 RBM1 ANK RBM2 S/T-kinase RBM1 ANK ZF1 RBM2 CD S/T ZF2 -kinaseCD RBM1 ANK ANK RBM2 S/T-kinase RBM1 RBM2 S/T-kinase RBM1 SAM RBM2 HD S/T-kinase RBM1 RBM1 RBM2 RBM2 S/T S/T-kinase -kinase RBM1 RBM2 S/T-kinase STYK PUG SAM STYK HD PUG STYK STYK PUG PUG RBM1 RBM2 S/T-kinase RBM1 RBM2 S/T-kinase ZF1 CD ZF2 CD SAMHD1 SAMHD1 SAM HD ANK UBL UBL ANK ANK UBL ANK ANK ZF1 UBL CD STYK PUG ZF2 CD SAM ANK ANK HD ANK ISG15 ISG15 UBL ANK UBL ANK ANK ANK STYK STYK PUG PUG STYK STYK PUG PUG STYK STYK PUG PUG UBL TM UBL STYK PUG ANK ANK ZF1 CD ZF2 CD ZF1 CD STYK PUG ZF2 CD ZF1 ZF1 CD CD STYK PUG ZF2 ZF2 CD CD SAM STYK STYK HD PUG PUG TM Tetherin Tetherin CYD STYK STYKCC PUG PUG UBL TM UBL CYD SAM HD CC TM ZF1 CD ZF2 CD CYD CC UBL ZF1 ZF1 UBL CD CD ZF2 ZF2 CD CD ZF1 CD ZF2 CD CYD ZF1 CD CC ZF2 CD SAM ZF1 CD HD ZF2 CD SAM ZF1 ZF1 TMCD CD HD ZF2 ZF2 CD CD SAM SAM HD HD Viperin Viperin SAM ZF1 CD ZF2 CD ZF1 ZF1 ZF1 CD CD CD ZF2 ZF2 ZF2 CD CD CD UBL UBL SAM ZF1 CD ZF2 CD CYD ZF1 CD CC ZF2 CD TM SAM SAM HD Family and domain organization of the major IFN-induced antiviral effectors (see REF. 8). ANK, ankyrin repeats; APOBEC3, UBL UBL UBL SAM UBL UBL UBL UBL UBL CYD SAM SAM HD HD CC apolipoprotein B mRNA-editing enzyme, catalytic polypeptide 3; ARF, SAM SAM ADP ribosylation HD HD factor; BB, B-box; BR, bromodomain; CBD, TM SAM SAM HD HD SAM HD SAM HD 2+ SAM SAM SAM HD HD HD Ca -binding domain; CC, coiled-coil domain; CD, cytidine deaminase SAM domain; CID, central interactive domain; COS, C- terminal CYD CC Nature Reviews | Immunology UBL SAM SAM UBL HD HD TM TM subgroup one signature; CYD, cytoplasmic domain; DYN, dynamin-like domain; TM TM EIF2AK, eukaryotic translation initiation factor 2α UBL UBL UBL UBL Nature Reviews | Immunology UBL UBL SAM UBL UBL kinase; FN3, fibronectin type 3; FIL, filamin-type immunoglobulin; HD, UBL UBL CYD helical domain; UBL UBL CC IFITM, interferon-inducible transmembrane UBL CYD UBL CC Nature Reviews | Immunology CYD CYD CC CC UBL UBL UBL UBL UBL UBL UBL UBL Nature Reviews | Immunology protein; ISG15, IFN-stimulated gene 15 kDa protein; LZ, leucine zipper; MATH, TM meprin and TNFR-associated factor homology; MX, UBL UBL SAM UBL UBL TM TM myxoma resistance protein; NHL, NHL repeat; OAS, 2ʹ-5ʹ oligoadenylate synthetase domain (catalytically inactive domains shown TM TM CYD CC TM TM TM Nature Reviews | Immunology TM in grey); P, palmitoylation site; PHD, plant homeodomain; PKR, IFN-induced, SAM RNA-activated TM TM TM protein kinase; PUG, protein kinase CYD CYD SAM CC CC SAM SAM CYD CYD CC CC CYD CYD CC CC CYD TM TM CC domain (containing a UBA or UBx domain); R, RING domain; RBM, RNA binding motif; SAM, radical S-adenosyl methionine domain; CYD CC CYD CYD CYD CC CC CC Nature Reviews | Immunology SAMHD1, SAM-domain- and HD-domain-containing protein 1; STYK, CYD CYD Ser/Thr/Tyr kinase CC CC domain; TM, transmembrane domain; SAM Nature Reviews | Immunology TRIM, tripartite motif protein; UBL, ubiquitin-like domain, ZF, zinc finger. SAM SAM SAM SAM SAM SAM SAM SAM SAM SAM SAM Nature Reviews | Immunology Natur Natur Nature Re e Re e Reviews views views ||| Immunology Immunology Immunology SAM SAM Nature Reviews | Immunology NATUR E R EVIEWS | IMMUNOLOGY VOLUME 12 | MAY 2012 | 377 Natur Nature Re e Reviews views || Immunology Immunology Natur Nature Re e Reviews views || Immunology Immunology Natur Nature Re e Reviews views || Immunology Immunology Nature Reviews | Immunology Nature Reviews | Immunology Nature Reviews | Immunology Natur Nature Re e Reviews views || Immunology Immunology © 2012 Macmillan Publishers Limited. All rights reserved Natur Nature Re e Reviews views || Immunology REVIEWS replication . Results from recent crystallography expe -r Virus iments suggest that disordered loops within an elongated Viral release MX1 helical ‘stalk’ may dock with negatively charged nucleocapsids to mediate entrapment . Viral entry Structural analogies with the MX proteins could also Tetherin underpin the antiviral activity reported for dynamin- like GBPs against vesicular stomatitis virus (VSV), IFITMs encephalomyocarditis virus, hepatitis C virus and 18,131 influenza A virus . Human GBP1, GBP3 and a novel Endosome Viral assembly splice isoform termed GBP3ΔC (which lacks part of or lysosome the C-terminal helical domain) (TABLE 1) appear to be Viperin dependent on GTP binding but not hydrolysis for their effects, suggesting that oligomerization is important for Uncoating ISG15 the antiviral activity of GBPs. This evolutionary adap - tation may allow GBPs to avoid viral antagonists such TRIM5α as the NS5B protein of hepatitis C virus, which can interfere with their catalytic activity . Protein APOBEC3 translation MXs Inhibiting viral replication. Once viruses uncoat, they SAMHD1 establish cytoplasmic or nuclear sites of replication RNA reverse transcription (which for Retroviridae includes chromosomal inte - PKR or gration). The landmark discoveries of IFN-induced, NOS2 RNA-activated protein kinase (PKR) and 2ʹ-5ʹ oligo- Nucleus adenylate synthase 1 (OAS1), OAS2 and OAS3 (and OASL in humans) provided early insights regard- GBP3ΔC RNA ing how viral RNA substrates are targeted (reviewed transcription in REF. 8). PKR possesses RNA-binding motifs at its RNase L Retroviral or ISG20 N-terminus that engage both double-stranded RNA integration Viral RNAs (dsRNA) and single-stranded RNA (ssRNA) (TABLE 3); the viral uncapped RNAs that are recognized by PKR NOS2 OAS ADAR1 often have limited duplexed regions and 5 ʹ triphosphate moieties, which enable the enzyme to distinguish them Figure 4 | Cell-autonomous mechanisms used by IFN-induced proteins against from host, capped RNA species . Once activated, PKR viruses. Multiple strategies are used by interferon (IFN)-inducible proteins to combat Nature Reviews | Immunology phosphorylates eukaryotic translation initiation fac - viruses. IFN-inducible effectors function at nearly every stage of the pathogen life tor 2α (EIF2α) to block viral and host protein tran- s cycle. For example, interferon-inducible transmembrane proteins (IFITMs) and lation, a process that is thought to be under intense tripartite motif proteins (TRIMs) act during viral entry and uncoating, and myxoma resistance proteins (MXs) block nucleocapsid transport. Inhibition of RNA reverse positive selection to avoid the emergence of viral mim - transcription, protein translation and stability is mediated by APOBEC3 ics of the substrate EIF2α . Likewise, the recognition (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide 3), SAMHD1 of dsRNA by OAS enzymes results in the production (SAM-domain- and HD-domain-containing protein 1), ADAR1 (adenosine deaminase, of 2ʹ-5ʹ oligoadenylates, which when polymerized ac- ti RNA-specific 1), NOS2 (nitric oxide synthase 2), OASs (2ʹ-5ʹ oligoadenylate vate the latent endoribonuclease RNase L to degrade synthases), RNase L, ISG20 (IFN-stimulated gene 20 kDa protein), PKR (IFN-induced, viral RNA transcripts. Lastly, the exonuclease ISG20 RNA-activated protein kinase) and ISG15. Finally, viperin and tetherin help to prevent (IFN-stimulated gene 20 kDa protein) degrades RNA viral assembly and release, respectively. Some of the effectors (such as MX proteins) transcripts belonging to VSV, influenza virus and appear to operate in both the nucleus and the cytosol (not shown). encephalomyocarditis virus . Some IFN-dependent enzymes edit viral RNAs and mouse MX2 are cytosolic proteins that target cyto- instead of degrading them. APOBEC3 (apolipo- plasmic viruses . Human MX1 exhibits the broadest protein B mRNA-editing enzyme, catalytic poly - range of antiviral activity, targeting all the infectious peptide 3) and ADAR1 (adenosine deaminase, genera of the Bunyaviridae family (that is, orthobunya- RNA-specific 1) are site-specific cytidine and adenosine viruses, hanta viruses, phleboviruses and nairoviruses) as deaminases, respectively. APOBEC3 converts cytidine to well as coxsackievirus and hepatitis B virus . This fits uridine in dsRNA, whereas ADAR1 catalyses the deami- 8,134 with its expression in human endothelial cells, hepa- to nation of adenosine to inosine . These incorporations cytes, plasma cytoid dendritic cells, peripheral bloo d lead to RNA destabilization and hypermutation after mononuclear cells and other myeloid cells. reverse transcription to cause lethal genome mutations in Current mechanistic models propose that GTPase- retroviruses such as HIV-1 (REF. 135). Different APOBEC driven MX protein oligomers form ring-like structures to isoforms (APOBEC3F and APOBEC3G) exhibit distinct 128,130 trap viral nucleocapsids and associated polymerases . mechanisms involving the processing of long terminal Such interactions may occur when MX proteins recog- repeats, and they may also interact with RNA and/or nize incoming viral ribonuclear particle complexes that the Gag protein from HIV-1 to prevent the packaging of 8,135 are destined for nuclear import or non-nuclear sites of these molecules into viral particles (FIG. 4). 378 | MAY 2012 | VOLUME 12 w w w.nature.com/reviews/immunol © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS Another IFN-inducible retroviral restriction factor The mature tetherin protein is a type II transmem- termed SAM-domain- and HD-domain-containing brane disulphide-linked dimer. Its C -terminal ecto- protein 1 (SAMHD1) was found more recently in domain is modified by a glycophosphatidylinositol 136–138 macrophages and dendritic cells , providing (GPI) linkage, and its N-terminal cytoplasmic domain some explanation as to why HIV -1 inefficiently trans- contains YxY motifs for binding the clathrin adaptor duces mononuclear phagocytes. SAMHD1 contains a proteins AP1 and AP2 during the endocytic internaliza - nucleotide-phosphohydrolase domain that hydrolyses tion of tethered virus for lysosomal delivery (TABLE 3). deoxynucleotides from the cellular poo (T l ABLE 3), and This topology may enable the association of tetherin depleting this nucleotide supply is currently posited to with lipid rafts and virion lipids so that it can be inco- r limit HIV -1 reverse transcriptase activity (FIG. 4). porated into HIV-1 particles. The secondary rather than Non-nucleotide targets are also subject to IFN- primary structure of tetherin is thought to dictate its mediated inhibition. The ubiquitin-like modifier ISG15 antiviral activity , with the N-terminal and coiled- restricts influenza viruses, herpesviruses, Sindbis virus, coil regions within the tetherin ectodomain minimally HIV-1, human papillomavirus (HPV) and Ebola virus required for viral retention (FIG. 4; TABLE 3). 139–141 in cells activated by type I IFNs , and many of these Viperin (also known as RSAD2) was originally –/– 139 viruses cause lethal infection in Isg15 mice . ISG15 shown to be induced by type I and II IFN signalling acts by conjugating target viral (and cellular) proteins in human cytomegalovirus-infected skin cells and in a process termed ISGylation . ISGylation substrates in mice infected with lymphocytic choriomeningi- include many newly synthesized viral proteins, such as tis virus . Viperin contains an S-adenosyl methio- the influenza A virus protein NS1 and the HPV capsid nine (SAM) domain and an N-terminal amphipathic proteins L1 and L2, which are needed for replication and helix that contributes to its antiviral activity by hel- p host evasion, and the HIV-1 protein Gag and the Ebola ing viperin to associate with ER membranes or lipid 151,152 virus protein VP40, which are involved in viral bud - droplets (FIG. 4; TABLE 3), where it interferes with 140,141 ding . ISGylation can interfere with modification of the assembly and egress of influenza virus and hepat-i these viral proteins by ubiquitin, which would otherwise tis C virus particles. This may occur through the dis- help to activate their functions . ruption of ER-derived lipid rafts that transport viral Nitrosylation is another post-translational modific-a envelope proteins to the plasma membrane, possibly tion that inhibits viruses. NO released by IFN-induced via the inhibition of farnesyl pyrophosphate synthase, NOS2 blocks DNA viruses — including poxviruses which is involved in cholesterol and isoprenoid sy- n 151,152 (such as ectromelia virus and vaccinia virus), herpes- thesis . Recent work also demonstrates that viperin viruses (such as HSV-1 and Epstein–Barr virus) and inhibits dengue virus, HIV-1 and West Nile virus, rhabdoviruses (such as VSV) — as well some RNA although whether it uses similar mechanisms remains 7,27,142–144 150,153 viruses (such as coxsackie B3 virus) . Where untested . examined, the loss of antiviral effector function in Numerous IFN-inducible restriction factors therefore –/– Nos2 mice coincided with heightened susceptibility target each stage of the viral life cycle in a variety of cell to viral infection (TABLE 2). The processes targeted by types, ensuring broad protective coverage to combat this NO include early and late viral protein synthesis, as welldi verse group of pathogens. as S-nitrosylation of structural proteins (in the case of VSV) or cysteine proteases (in the case of coxsackie B3 Conclusions and future directions virus). They also extend to DNA replication (in the case An avalanche of information has emerged over the last of vaccinia virus) and to RNA or DNA synthesis via the 15 years on the sensory apparatus and signalling ca- s inhibition of an immediate-early gene encoding the trans- cades that mobilize innate immunity in response to 27,142–144 6 activator Zta (in the case of Epstein–Barr virus) . infection . By contrast, little is known about the cell- Thus, replicative viral DNA and RNA, as well as viral autonomous effector mechanisms that confer steriliz- proteins, serve as direct targets for IFN-mediated ing immunity. How do we actually kill intracellular modification and inactivation. pathogens, or at least restrict their growth? Remarkably, such mechanisms seem to operate across most vertebrate Preventing viral assembly, budding and release. cells, an inheritance foretold by the defence repertoires 1,2 Following replication, viral DNA, RNA and stru -c of plants and lower organisms , but with the added fea- tural proteins are packaged into nascent virions for tures of expansive diversification and induction by IFNs 3,8 budding and release. At least two recently described in larger, long-lived chordates . IFN-induced proteins — tetherin and viperin — affect Recent applications of systems biology have begun late-stage export. to unearth new IFN-induced antiviral factors (such as Tetherin (also known as CD317 and BST2) is a viral IFITMs) , and genome-wide in silico identification cou- restriction factor that prevents the release of HIV-1 pled with traditional loss-o -f function approaches has particles from infected macrophages, where it also revealed proteins with novel antibacterial activities (such ISGylation 145,146 16 The attachment of the serves as a target for the HIV-1 protein Vpu . In as GBPs) . This list will continue to grow as we probe the ubiquitin-like modifier ISG15 to addition, it prevents the release of filovirus, arenavirus interface between vertebrate hosts and microbial patho- either pathogen or host protein 154,155 and herpesvirus particles in response to type I IFN or gens using large-scale unbiased methods , in some targets to regulate their IFNγ stimulation in macrophages and plasmacytoid cases with the assistance of government centres dedicated function rather than stimulate degradation. dendritic cells. to the systematic study of infection (see REF. 156). NATUR E R EVIEWS | IMMUNOLOGY VOLUME 12 | MAY 2012 | 379 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS As next-generation informatics takes hold, we are genes is more than the sum of their individual parts, one MicroRNAs 154–156 likely to find new IFN-inducible proteins with unique and of the founding doctrines of systems biology . Single-stranded RNA molecules of approximately perhaps unusual functions in host defence. For example, Other outstanding questions include the identity of 21–23 nucleotides in length such proteins could protect the nucleus from retroviral the membrane signals, signatures and structures that that are thought to regulate the insertion or bacterial factors ; defend gap junctions allow the recruitment of effectors to intact or damaged expression of other genes. 158,159 from bacterial cell- to-cell spread ; alter microbial or pathogen compartments for their eventual removal, a host cell metabolism ; participate in pathogen-selective topic in which the IFN-inducible IRGs and GBPs will forms of autophagy ; or use different forms of nucleo- play a leading part. 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Interferon-inducible effector mechanisms in cell-autonomous immunity

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Interferon-inducible effector mechanisms in cell-autonomous immunity

Interferon-inducible effector mechanisms in cell-autonomous immunity

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