Apicomplexan F‐actin is required for efficient nuclear entry during host cell invasionDel Rosario, Mario; Periz, Javier; Pavlou, Georgios; Lyth, Oliver; Latorre‐Barragan, Fernanda; Das, Sujaan; Pall, Gurman S; Stortz, Johannes Felix; Lemgruber, Leandro; Whitelaw, Jamie A; Baum, Jake; Tardieux, Isabelle; Meissner, Markus
doi: 10.15252/embr.201948896pmid: 31584242
The obligate intracellular parasites Toxoplasma gondii and Plasmodium spp. invade host cells by injecting a protein complex into the membrane of the targeted cell that bridges the two cells through the assembly of a ring‐like junction. This circular junction stretches while the parasites apply a traction force to pass through, a step that typically concurs with transient constriction of the parasite body. Here we analyse F‐actin dynamics during host cell invasion. Super‐resolution microscopy and real‐time imaging highlighted an F‐actin pool at the apex of pre‐invading parasite, an F‐actin ring at the junction area during invasion but also networks of perinuclear and posteriorly localised F‐actin. Mutant parasites with dysfunctional acto‐myosin showed significant decrease of junctional and perinuclear F‐actin and are coincidently affected in nuclear passage through the junction. We propose that the F‐actin machinery eases nuclear passage by stabilising the junction and pushing the nucleus through the constriction. Our analysis suggests that the junction opposes resistance to the passage of the parasite's nucleus and provides the first evidence for a dual contribution of actin‐forces during host cell invasion by apicomplexan parasites.
A nuclear licence to silence transposonsGould, Poppy A; Rowe, Helen M
doi: 10.15252/embr.201949262pmid: 31621182
Transposon silencing requires the histone methyltransferase SETDB1. In this issue of EMBO Reports, Tsusaka et al [1] and Osumi et al [2] illustrate how the cofactor ATF7IP and its fly homolog Windei (Wde) regulate the methyltransferase function of SETDB1 through its nuclear licensing. The new insight gained from these two articles will shift how we think about epigenetic regulation and its multiple layers of control.
Optogenetic inhibition of Delta reveals digital Notch signalling output during tissue differentiationViswanathan, Ranjith; Necakov, Aleksandar; Trylinski, Mateusz; Harish, Rohit Krishnan; Krueger, Daniel; Esposito, Emilia; Schweisguth, Francois; Neveu, Pierre; De Renzis, Stefano
doi: 10.15252/embr.201947999pmid: 31668010
Spatio‐temporal regulation of signalling pathways plays a key role in generating diverse responses during the development of multicellular organisms. The role of signal dynamics in transferring signalling information in vivo is incompletely understood. Here, we employ genome engineering in Drosophila melanogaster to generate a functional optogenetic allele of the Notch ligand Delta (opto‐Delta), which replaces both copies of the endogenous wild‐type locus. Using clonal analysis, we show that optogenetic activation blocks Notch activation through cis‐inhibition in signal‐receiving cells. Signal perturbation in combination with quantitative analysis of a live transcriptional reporter of Notch pathway activity reveals differential tissue‐ and cell‐scale regulatory modes. While at the tissue‐level the duration of Notch signalling determines the probability with which a cellular response will occur, in individual cells Notch activation acts through a switch‐like mechanism. Thus, time confers regulatory properties to Notch signalling that exhibit integrative digital behaviours during tissue differentiation.
ELAVL2‐directed RNA regulatory network drives the formation of quiescent primordial folliclesKato, Yuzuru; Iwamori, Tokuko; Ninomiya, Youichirou; Kohda, Takashi; Miyashita, Jyunko; Sato, Mikiko; Saga, Yumiko
doi: 10.15252/embr.201948251pmid: 31657143
Formation of primordial follicles is a fundamental, early process in mammalian oogenesis. However, little is known about the underlying mechanisms. We herein report that the RNA‐binding proteins ELAVL2 and DDX6 are indispensable for the formation of quiescent primordial follicles in mouse ovaries. We show that Elavl2 knockout females are infertile due to defective primordial follicle formation. ELAVL2 associates with mRNAs encoding components of P‐bodies (cytoplasmic RNP granules involved in the decay and storage of RNA) and directs the assembly of P‐body‐like granules by promoting the translation of DDX6 in oocytes prior to the formation of primordial follicles. Deletion of Ddx6 disturbs the assembly of P‐body‐like granules and severely impairs the formation of primordial follicles, indicating the potential importance of P‐body‐like granules in the formation of primordial follicles. Furthermore, Ddx6‐deficient oocytes are abnormally enlarged due to misregulated PI3K‐AKT signaling. Our data reveal that an ELAVL2‐directed post‐transcriptional network is essential for the formation of quiescent primordial follicles.
Caspase‐11 counteracts mitochondrial ROS‐mediated clearance of Staphylococcus aureus in macrophagesKrause, Kathrin; Daily, Kylene; Estfanous, Shady; Hamilton, Kaitlin; Badr, Asmaa; Abu Khweek, Arwa; Hegazi, Rana; Anne, Midhun NK; Klamer, Brett; Zhang, Xiaoli; Gavrilin, Mikhail A; Pancholi, Vijay; Amer, Amal O
doi: 10.15252/embr.201948109pmid: 31637841
Methicillin‐resistant Staphylococcus aureus (MRSA) is a growing health concern due to increasing resistance to antibiotics. As a facultative intracellular pathogen, MRSA is capable of persisting within professional phagocytes including macrophages. Here, we identify a role for CASP11 in facilitating MRSA survival within murine macrophages. We show that MRSA actively prevents the recruitment of mitochondria to the vicinity of the vacuoles they reside in to avoid intracellular demise. This process requires CASP11 since its deficiency allows increased association of MRSA‐containing vacuoles with mitochondria. The induction of mitochondrial superoxide by antimycin A (Ant A) improves MRSA eradication in casp11−/− cells, where mitochondria remain in the vicinity of the bacterium. In WT macrophages, Ant A does not affect MRSA persistence. When mitochondrial dissociation is prevented by the actin depolymerizing agent cytochalasin D, Ant A effectively reduces MRSA numbers. Moreover, the absence of CASP11 leads to reduced cleavage of CASP1, IL‐1β, and CASP7, as well as to reduced production of CXCL1/KC. Our study provides a new role for CASP11 in promoting the persistence of Gram‐positive bacteria.
Parkin‐mediated ubiquitylation redistributes MITOL/March5 from mitochondria to peroxisomesKoyano, Fumika; Yamano, Koji; Kosako, Hidetaka; Kimura, Yoko; Kimura, Mayumi; Fujiki, Yukio; Tanaka, Keiji; Matsuda, Noriyuki
doi: 10.15252/embr.201947728pmid: 31602805
Ubiquitylation of outer mitochondrial membrane (OMM) proteins is closely related to the onset of familial Parkinson's disease. Typically, a reduction in the mitochondrial membrane potential results in Parkin‐mediated ubiquitylation of OMM proteins, which are then targeted for proteasomal and mitophagic degradation. The role of ubiquitylation of OMM proteins with non‐degradative fates, however, remains poorly understood. In this study, we find that the mitochondrial E3 ubiquitin ligase MITOL/March5 translocates from depolarized mitochondria to peroxisomes following mitophagy stimulation. This unusual redistribution is mediated by peroxins (peroxisomal biogenesis factors) Pex3/16 and requires the E3 ligase activity of Parkin, which ubiquitylates K268 in the MITOL C‐terminus, essential for p97/VCP‐dependent mitochondrial extraction of MITOL. These findings imply that ubiquitylation directs peroxisomal translocation of MITOL upon mitophagy stimulation and reveal a novel role for ubiquitin as a sorting signal that allows certain specialized proteins to escape from damaged mitochondria.
A nuclear licence to silence transposonsGould, Poppy A; Rowe, Helen M
doi: 10.15252/embr.201949262pmid: 31621182
Transposon silencing requires the histone methyltransferase SETDB1. In this issue of EMBO Reports, Tsusaka et al [1] and Osumi et al [2] illustrate how the cofactor ATF7IP and its fly homolog Windei (Wde) regulate the methyltransferase function of SETDB1 through its nuclear licensing. The new insight gained from these two articles will shift how we think about epigenetic regulation and its multiple layers of control.