Plant Physiology

Cheung, Alice Y.; Qu, Li-Jia; Russinova, Eugenia; Zhao, Yunde; Zipfel, Cyril

doi: 10.1104/pp.20.00275pmid: 32253323

Cheung, Alice Y.; Qu, Li-Jia; Russinova, Eugenia; Zhao, Yunde; Zipfel, Cyril

doi: 10.1104/pp.20.00275pmid: 32253323

The ability of cells to sense and respond to endogenous cues as well as cues from neighboring cells and tissues underlies the life and death of cells, their growth and proliferation, differentiation into tissues, and ultimately development into morphologically diverse organisms. Being able to sense and respond to an ever-changing environment allows organisms to thrive, propagate, and overcome life-threatening challenges and thus is critical for their survival as individuals and as species. The study of signal transduction in plants has expanded dramatically from the early efforts to define the basic components of signaling by the most classically known hormones (e.g. auxin, abscisic acid, ethylene, and brassinosteroid) and environmental stresses. These studies have led to paradigms for different molecular strategies and provided the foundation for recent efforts to study the expanding world of signals, such as endogenous peptides, and inform the need to integrate linearity in established signaling pathways into connected networks. Breakthroughs in approaches, aided by escalating computational power, have enabled plant signal transduction research to advance with unprecedented breadth and depth, addressing diverse processes to reveal, for example, the dynamic of signaling and structural perspectives at the single-molecule and atomic levels. This Focus Issue on Receptors and Signaling addresses some of the most important advances and new landmarks in the field. In addition to commissioned Updates by experts in their respective topics, several research articles highlight recent accomplishments in these areas. Ubiquitination/26S proteasome-regulated proteolysis, firmly established for auxin signaling (Leyser 2018), continues to be identified as central to an ever-increasing number of signaling pathways. Tal et al. (2020) provide an overview of major hormone signaling pathways mediated by regulated proteolysis. This review also focuses on the recently identified phytohormone strigolactone, whose receptor DWARF14 is surprisingly also an enzyme that converts its ligand into nonbioactive products, and highlights recent structural insights. The classical topics in hormone signaling, such as for auxin and abscisic acid, continue to be areas of active research. Fernandez et al. (2020) report additional complexity in abscisic acid signaling mediated by regulated proteolysis in different subcellular compartments. Ramos Baĭez et al. (2020) demonstrate the use of synthetic and heterologous systems to dissect the molecular mechanisms of auxin signaling in maize (Zea mays). This latter system is transferable and potentially useful for functional analysis of putative auxin signaling components from new sources. How the ubiquitous second messenger Ca2+ is decoded into specific responses remains an enigma. Liu et al. (2020) report a theoretical simple gene expression system to uncover a design principle with which the Ca2+ signal is decoded into specific gene expression responses. Signaling in defense responses has seen the most explosive advances in the last two decades. Li et al. (2020) provide an interesting overview on how studies of plant immunity have come into their own over the decades with the identification of common grounds with animal immunity as well as unique strategies and components. The list of danger signals, including pathogen-associated molecular patterns (PAMPs) from microbes and pests (nonself) and damage-associated molecular patterns (DAMPs) from damaged host cells (modified self), is expansive and still growing. Plants employ both cell surface-localized and intracellular immune receptors to detect nonself and modified-self molecules and activate immune responses. Surface-localized immune receptors, also called pattern recognition receptors (PRRs), are either receptor kinases (RKs; which include a ligand-binding ectodomain, a single-pass transmembrane domain, and an intracellular kinase domain) or receptor proteins (RPs; which share a similar domain organization with RKs but lack an intracellular kinase domain). Pathogens can be sensed by nucleotide-binding leucine-rich repeats (NLRs) that recognize directly or indirectly secreted proteins inside host plant cells. Recent structural studies have uncovered the molecular mechanisms underlying how plant immune receptors perceive their ligands and become activated. These studies, reviewed by Wang and Chai (2020), illustrate how different types of PRR ectodomains mediate the perception of distinct microbial or plant-derived ligands and how ligand binding induces complex formation with coreceptors that are required for the activation of downstream immune signaling. Recent studies, including those based on cryo-electron microscopy, have demonstrated that some plant NLRs form supramolecular structures, so-called resistosomes (analogous to the inflammasome built by mammalian NLRs), that are required for immune-induced cell death. The study of plant PRRs has also highlighted general principles of RK/RP-based signaling. Albert et al. (2020) review different types of plant PRRs and their ligands, how PRR complexes are regulated, and current knowledge of immune signaling downstream of plant PRRs. The area remains extraordinarily active. For instance, one of the best studied plant PRRs is the Leu-rich RK FLS2 that perceives the PAMP flg22, a conserved peptide epitope from bacterial flagellin. Collins et al. (2020) show that the abundances of Arabidopsis (Arabidopsis thaliana) FLS2 and its coreceptor BAK1/SERK3 are controlled by the trans-Golgi network-associated clathrin adaptor EPSIN1, which correlates with a positive role of EPSIN1 in antibacterial immunity against the plant pathogen Pseudomonas syringae. Li et al. (2020) discuss the growing number of identified and potential plant DAMPs, including extracellular ATP (eATP), extracellular NADP [eNAD(P)], and their receptors and/or candidate receptors. For instance, plant PRRs can detect modified-self molecules such as eATP. The first example of a plant eATP receptor is an L-type lectin RK, P2K1 (Choi et al., 2014). As reviewed by Li et al. (2020), L-type lectin RKs are also potential receptors for eNAD(P). Important gaps still exist in our knowledge of how plant cells are able to distinguish between foes (pathogens) and friends (beneficials), especially when plant receptors and microbial ligands involved in root symbioses with nitrogen-fixing rhizobial bacteria or mycorrhizal fungi show striking similarities with those involved in PRR-mediated immune signaling. Chiu and Paszkowski (2020) provide a comprehensive review of current knowledge of the ligands, receptors, and downstream signaling involved in the perception of symbionts and the establishment of symbioses that ultimately contribute to an optimal plant nutrition. Following its first identification in yeast, the evolutionarily conserved Target of Rapamycin (TOR) has been functionally characterized in yeast, plants, and mammals. An atypical Ser/Thr protein kinase, TOR mediates protein phosphorylation to integrate different internal and external signals to control multiple developmental processes as well as plant responses to a variety of stresses. Focusing on plant adaptation to nutrient deficiency and abiotic stresses, Fu et al. (2020) review the mechanisms of two major ways that TOR signaling adapts to abiotic stresses in plants: cross talk with abscisic acid signaling and inducing autophagy. They also consider potential regulators and downstream targets of TOR and reflect on future research directions. With a broader perspective, Lamers et al. (2020) consider how plants survive under an ever-changing environment where signals are abundant, diverse, and often simultaneous. This article reviews current knowledge for sensing different abiotic stresses, ranging from extremes in temperature and water supplies. It also evaluates the status of established and recently introduced sensors and/or potential sensors and considers a potential nexus that integrates and dispatches signals to cellular responses. An area of rapid growth is in the identification of large and diverse families of peptides as signals. In the past decade, the biological functions of these signal peptides have been widely studied, and many are involved in the development of different cell types/organs/tissues, such as CLE peptides in vascular differentiation and stem cell fate determination, and in various cell-cell communication processes, such as Rapid Alkalinization Factor (RALF) peptides that play roles in plant-pathogen and male-female interactions. Receptors for these peptides are still emerging and, together with their peptide ligands, a number have been structurally characterized, considerably advancing our understanding of the activation and signal transduction of receptor-peptide complexes. The importance of this emerging area is underscored by several Updates and a research article. Fukuda and Hardtke (2020) review the importance of CLE peptide-related signaling pathways during development of the vascular tissues in Arabidopsis. They address the complexity of multiple intersecting pathways as well as their interaction with plant hormones and environmental stresses. Jourquin et al. (2020) highlight the diverse roles played by CLE peptides in lateral root initiation. They also discuss a multitude of other peptides, diverse in structure but all important to the final root architecture, to highlight that current knowledge about peptide involvement in development is only the tip of the iceberg. In their research article, Berckmans et al. (2020) examine the CLE40 peptide, which in differentiated columella cells is perceived by the ACR4-CLV1 receptor complex. It was previously hypothesized that blocking the movement of the transcription factor WOX5 from the quiescent center to the adjacent cell layer regulates the differentiation of the columella stem cells. Berckmans et al. (2020) report findings that lead them to propose an alternate model in which the main function of CLE40 is to correctly position the quiescent center where WOX5 functions, supporting the idea that the regulation of root stem cells is achieved by the complex interaction of two antagonistic pathways. RALFs are a family of peptide regulators discovered in the early 1980s that reemerged in recent years as an area of intense interest. This is largely driven by their identification as ligands for the FERONIA RK and its coreceptor, the glycosylphosphatidylinositol-anchored protein LLG1. FERONIA RK is a member of the CrRLKL1 RK family and has been reviewed extensively in recent years (Li et al., 2016; Franck et al., 2018) and in several Updates here. Blackburn et al. (2020) weave a historical perspective on the discovery of RALFs with an account of the current status of these peptides as ligands for CrRLKL1 RK-LLG coreceptor complexes. They review different functional roles mediated by these RALF-RK complexes and current mechanistic understanding about the signaling processes from a large number of biological, biochemical, and structural studies. Many plant RKs, diverse in sequence and physiological functions, require a different RK as a coreceptor to perceive and transmit signals, and these coreceptors are often common to different pathways. In general, coreceptors have a much smaller extracellular domain compared with their ligand-binding RK partners. Gou and Li (2020) discuss recent progress and outstanding questions in paired RK-mediated signal transduction pathways and their roles in plant development. They reviewed BAK1 and homologous SERKs and their partnership with at least nine different RKs in a variety of signaling pathways controlling myriad processes. Other partnerships, such as CLV3 signaling and involving coreceptors CLAVATA3 INSENSITIVE RECEPTOR KINASES (CIKS), are also discussed. As knowledge mounts and methods improve in sophistication, the obvious consideration for researchers focused on signaling processes is to obtain an understanding that closely approximates the actual environment where these processes take place. In this regard, together with the cell wall, the plasma membrane is a critical barrier that determines the identity of a cell and its communication strategies with the outside world. Evidence suggests that, in plants, the plasma membrane with membrane-embedded receptors is highly compartmentalized and lateral segregation of proteins and lipids is critical for cell surface signaling, modulating signal perception, specificity, and integration. Lipid-protein interaction in membranes has started to attract attention from plant scientists in relation to its role in membrane protein complex assembly, stability, and function. These effects have been attributed mainly to interactions of the receptors with lipids mediated by protein scaffolds. It is believed that physiologically relevant processes occurring in membranes involve an intense coordination of multiple lipid-protein interactions. Since the organization and dynamics of membranes have considerable impact on membrane protein structure and function, the development and characterization of experimental tools to analyze these aspects of membranes assume significance in plant research. Jaillais and Ott (2020) review the current knowledge of membrane nanodomains in the plant plasma membrane and their functional importance. They also assess the roles of lipids, the cell wall, and the cytoskeleton in shaping this diverse plasma membrane landscape and discuss plausible scenarios for the functional importance of protein nanoclustering in signal transduction. Plants encode hundreds of putative cell surface receptors and thousands of secreted peptides that can be potentially their ligands. The study of how natural ligands influence the behavior of receptors can be challenging, as there is an enormous number of possible peptide ligand-RK pairs, ligands can be promiscuous in their binding, and one receptor can recognize several peptides. Moreover, different ligand-receptor interactions often trigger a plethora of outcomes, which depend on the cellular context. Therefore, assessing ligand-receptor interactions requires more integrative and quantitative approaches, including biophysical methods to measure membrane receptor dynamics and oligomerization state upon ligand binding. Sandoval and Santiago (2020) overview the state-of-the-art in vitro ligand-binding assays used to investigate receptor-ligand interactions. Among these, new structure-based ligand-binding technologies have emerged as powerful methods to uncover key residues and conformational changes of the receptors upon ligand binding. Together with new instruments and technologies, the options are expanding for protocols that use small amounts of unmodified receptor proteins and ligands. We hope that in capturing a snapshot of recent achievements in the field, the work presented here will inspire future efforts while also underscoring the impact of cumulative knowledge from a large research community in a rapidly advancing a field. With a number of articles submitted to the Focus Issue still at various stages of the review process, we anticipate that this Focus topic will be further enriched in the near future by these and other studies in related areas recorded in the online collection. LITERATURE CITED Albert I , Hua C, Nurnberger T, Pruitt RN, Zhang L( 2020 ) Surface sensor systems in plant immunity . Plant Physiol 182 : 1582 – 1596 Google Scholar Crossref Search ADS PubMed WorldCat Berckmans B , Kirschner G, Gerlitz N, Stadler R, Simon R( 2020 ) CLE40 signalling regulates root stem cell fate . Plant Physiol 182 : 1776 – 1792 Google Scholar Crossref Search ADS PubMed WorldCat Blackburn MR , Haruta M, Moura DS( 2020 ) Twenty years of progress in physiological and biochemical investigation of RALF peptides . Plant Physiol 182 : 1657 – 1666 Google Scholar Crossref Search ADS PubMed WorldCat Chiu CH , Paszkowski U( 2020 ) Receptor-like kinases sustain symbiotic scrutiny . Plant Physiol 182 : 1597 – 1612 Google Scholar Crossref Search ADS PubMed WorldCat Choi J , Tanaka K, Cao Y, Qi Y, Qiu J, Liang Y, Lee SY, Stacey G( 2014 ) Identification of a plant receptor for extracellular ATP . Science 343 : 290 – 294 Google Scholar Crossref Search ADS PubMed WorldCat Collins CA , LaMontagne ED, Anderson JC, Ekanayake G, Clarke AS, Bond LN, Salamango DJ, Cornish PV, Peck SC, Heese A( 2020 ) EPSIN1 modulates the plasma membrane abundance of FLAGELLIN SENSING2 for effective immune responses . Plant Physiol pp.01172.2019 Google Scholar OpenURL Placeholder Text WorldCat Fernandez MA , Belda-Palazon B, Julian J, Coego A, Lozano-Juste J, Inigo S, Rodriguez L, Bueso E, Goossens A, Rodriguez RL( 2020 ) RBR-type E3 ligases and the Ub-conjugating enzyme UBC26 regulate ABA receptor levels and signaling . Plant Physiol 182 : 1723 – 1742 Google Scholar Crossref Search ADS PubMed WorldCat Franck CM , Westermann J, Boisson-Dernier A( 2018 ) Plant malectin-like receptor kinases: From cell wall integrity to immunity and beyond . Annu Rev Plant Biol 69 : 301 – 328 Google Scholar Crossref Search ADS PubMed WorldCat Fu L , Wang P, Xiong Y( 2020 ) Target of Rapamycin signaling in plant stress responses . Plant Physiol 182 : 1613 – 1623 Google Scholar Crossref Search ADS PubMed WorldCat Fukuda H , Hardtke CS( 2020 ) Peptide signaling pathways in vascular differentiation . Plant Physiol 182 : 1636 – 1644 Google Scholar Crossref Search ADS PubMed WorldCat Gou X , Li J( 2020 ) Receptor and coreceptor: Paired RLKs perceive extracellular signals to control plant development . Plant Physiol 182 : 1667 – 1681 Google Scholar Crossref Search ADS PubMed WorldCat Jaillais Y , Ott T( 2020 ) The nanoscale organization of the plasma membrane and its importance in signaling: A proteolipid perspective . Plant Physiol 182 : 1682 – 1696 Google Scholar Crossref Search ADS PubMed WorldCat Jourquin J , Fukaki H, Beeckman T( 2020 ) Peptide-receptor signaling controls lateral root development . Plant Physiol 182 : 1645 – 1656 Google Scholar Crossref Search ADS PubMed WorldCat Lamers J , van der Meer T, Testerink C( 2020 ) How plants sense and respond to stressful environments . Plant Physiol 182 : 1624 – 1635 Google Scholar Crossref Search ADS PubMed WorldCat Leyser O ( 2018 ) Auxin signaling . Plant Physiol 176 : 465 – 479 Google Scholar Crossref Search ADS PubMed WorldCat Li C , Wu HM, Cheung AY( 2016 ) FERONIA and her pals: Functions and mechanisms . Plant Physiol 171 : 2379 – 2392 Google Scholar Crossref Search ADS PubMed WorldCat Li Q , Wang C, Mou Z( 2020 ) Perception of damaged self in plants . Plant Physiol 182 : 1545 – 1565 Google Scholar Crossref Search ADS PubMed WorldCat Liu J , Lenzoni G, Knight MR( 2020 ) Design principles for decoding calcium signals to generate specific gene expression via transcription . Plant Physiol 182 : 1743 – 1761 Google Scholar Crossref Search ADS PubMed WorldCat Ramos Báez R , Buckley Y, Yu H, Chen Z, Gallavotti A, Nemhauser JL, Moss BL( 2020 ) A synthetic approach reveals a highly sensitive maize auxin response circuit . Plant Physiol 182 : 1713 – 1722 Google Scholar Crossref Search ADS PubMed WorldCat Sandoval PJ , Santiago J( 2020 ) In vitro analytical approaches to study plant ligand-receptor interactions . Plant Physiol 182 : 1697 – 1712 Google Scholar Crossref Search ADS PubMed WorldCat Tal L , Anleu Gil MX, Guercio AM, Shabek N( 2020 ) Structural aspects of plant hormone signal perception and regulation by ubiquitin ligases . Plant Physiol 182 : 1537 – 1544 Google Scholar Crossref Search ADS PubMed WorldCat Wang J , Chai J( 2020 ) Structural insights into the plant immune receptors PRRs and NLRs . Plant Physiol 182 : 1566 – 1581 Google Scholar Crossref Search ADS PubMed WorldCat Author notes www.plantphysiol.org/cgi/doi/10.1104/pp.20.00275 © 2020 American Society of Plant Biologists. All Rights Reserved. © The Author(s) 2020. Published by Oxford University Press on behalf of American Society of Plant Biologists. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Julkowska, Magdalena M.

doi: 10.1104/pp.20.00001pmid: 32253324

Developmental and environmental changes are communicated systemically throughout the plant by various signals, ranging from electric currents to plant hormones. As the responses elicited by the systemic signals depend on the tissue and subcellular context, the signal needs to be adjusted at every scale, which can be achieved by regulating the abundance of receptor proteins (Guerra and Callis 2012). Regulation of hormone receptor abundance controls the magnitude of the response to hormones. Numbers of hormone receptors are reduced by tagging with ubiquitin residues, which targets the receptor proteins for degradation (Kelley and Estelle 2012). Once the protein is ubiquitinylated, degradation can proceed either through the 26S proteasome (Stone 2014) or the endosomal sorting complex required for transport (Gao et al., 2017). The ubiquitin tag is added to the substrate protein through the coordinated action of E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme, and E3 ubiquitin ligase (Shu and Yang, 2017). The perception of the stress-related abscisic acid (ABA) hormone was previously found to be regulated by the E3 ligase RING FINGER OF SEED LONGEVITY (RSL1; Belda-Palazon et al., 2016). RSL1 protein carries a C-terminal transmembrane domain, which tethers the E3 ligase to the plasma membrane, where it decorates ABA receptors PYR1 and PYL1 with ubiquitin tags (Bueso et al., 2014), initiating degradation in the vacuole mediated by the endosomal sorting complex required for transport (Belda-Palazon et al., 2016). While the Arabidopsis (Arabidopsis thaliana) genome contains 10 members of the RSL1/RFA (RING finger ABA-related) family, their contribution to the regulation of ABA receptor abundance is unknown. In the current issue of Plant Physiology, Fernandez et al. (2020) examine other members of RSL1/RFA family for their potential roles in regulating ABA perception. The group examined five members of the family (RFA1–RFA5), which lacked the C-terminal transmembrane domain. The in silico study of transcript abundance revealed that RFA1 and RFA4 were expressed in the same tissues and conditions as the ABA receptors, suggesting possible interactions between the RFAs and PYR/PYL. Fernandez et al. (2020) showed that both E3 ligases were interacting with ABA receptors using split yellow fluorescent protein/luciferase and pull-down assays. While RFA4 interacted with ABA receptors exclusively in the nucleus, the interaction between ABA receptors and RFA1 was observed in the nucleus and the cytosol. The yeast two-hybrid screen for the partner E2 ligase revealed that UBIQUITIN CONJUGATING ENZYME 26 (UBC26) interacts with RFA4 and ABA receptors in the nucleus. As expected, the ubc26 and rfl1/4 mutant lines showed higher levels of the PYR/PYL receptor proteins and were hypersensitive to ABA. However, ABA treatment still induced the degradation of ABA receptors in rfl1/4 mutant lines, revealing that the receptor level is regulated by multiple pathways working in parallel. The work by Fernandez et al. (2020) shows that ABA receptor turnover is regulated by multiple E3 ubiquitin ligases: RSL1 targets the ABA receptors at the plasma membrane, RFA1 targets the nuclear and cytosolic PYL/PYR proteins, and RFA4 exclusively targets nuclear ABA receptors. The interactions between hormone receptors, E3, and E2 ligases illustrate the complexity of hormone signaling cascades, where the hormone perception can be modulated not only at the tissue level but at the subcellular level, by regulating the receptor abundance. Tapping into this complexity between the ABA receptors and the E3 ubiquitin ligases might be an exciting target in future breeding programs for increased resilience of plants to biotic and abiotic stressors, finetuning the plant’s stress response without compromising plant performance under nonstress conditions. LITERATURE CITED Belda-Palazon B , Rodriguez L, Fernandez MA, Castillo M-C, Anderson EM, Gao C, Gonzalez-Guzman M, Peirats-Llobet M, Zhao Q, De Winne N, et al. ( 2016 ) FYVE1/FREE1 interacts with the PYL4 ABA receptor and mediates its delivery to the vacuolar degradation pathway . Plant Cell 28 : 2291 – 2311 Google Scholar Crossref Search ADS PubMed WorldCat Bueso E , Rodriguez L, Lorenzo-Orts L, Gonzalez-Guzman M, Sayas E, Muñoz-Bertomeu J, Ibañez C, Serrano R, Rodriguez PL ( 2014 ) The single-subunit RING-type E3 ubiquitin ligase RSL1 targets PYL4 and PYR1 ABA receptors in plasma membrane to modulate abscisic acid signaling . Plant J 80 : 1057 – 1071 Google Scholar Crossref Search ADS PubMed WorldCat Fernandez MA , Belda-Palazon B, Julian J, Coego A, Lozano-Juste J, Inigo S, Rodriguez L, Bueso E, Goossens A, Rodriguez PL ( 2020 ) RBR-type E3 ligases and the Ub-conjugating enzyme UBC26 regulate ABA receptor levels and signaling . Plant Physiol 182 : 1723 – 1742 Google Scholar Crossref Search ADS PubMed WorldCat Gao C , Zhuang X, Shen J, Jiang L ( 2017 ) Plant ESCRT complexes: Moving beyond endosomal sorting . Trends Plant Sci 22 : 986 – 998 Google Scholar Crossref Search ADS PubMed WorldCat Guerra DD , Callis J ( 2012 ) Ubiquitin on the move: The ubiquitin modification system plays diverse roles in the regulation of endoplasmic reticulum- and plasma membrane-localized proteins . Plant Physiol 160 : 56 – 64 Google Scholar Crossref Search ADS PubMed WorldCat Kelley DR , Estelle M ( 2012 ) Ubiquitin-mediated control of plant hormone signaling . Plant Physiol 160 : 47 – 55 Google Scholar Crossref Search ADS PubMed WorldCat Shu K , Yang W ( 2017 ) E3 ubiquitin ligases: Ubiquitous actors in plant development and abiotic stress responses . Plant Cell Physiol 58 : 1461 – 1476 Google Scholar Crossref Search ADS PubMed WorldCat Stone SL ( 2014 ) The role of ubiquitin and the 26S proteasome in plant abiotic stress signaling . Front Plant Sci 5 : 135 Google Scholar Crossref Search ADS PubMed WorldCat Author notes 2 Senior author. www.plantphysiol.org/cgi/doi/10.1104/pp.20.00001 © 2020 American Society of Plant Biologists. All Rights Reserved. © The Author(s) 2020. Published by Oxford University Press on behalf of American Society of Plant Biologists. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Julkowska, Magdalena M.

doi: 10.1104/pp.20.00001pmid: 32253324

Lanctot, Amy; Taylor-Teeples, Mallorie; Oki, Erika A.; Nemhauser, Jennifer L.

doi: 10.1104/pp.19.01474pmid: 31937684

Dear Editors, AUXIN RESPONSE FACTOR (ARF) transcription factors diverged basally in evolution (Mutte et al., 2018) and there is evidence that they provide specificity in auxin-regulated genetic networks (e.g. Wilmoth et al., 2005; Krogan et al., 2016). Studies contrasting the binding behavior of Class A (“activator”) and Class B (“repressor”) ARFs (Boer et al., 2014; O’Malley et al., 2016; Galli et al., 2018) found distinct promoter preferences between classes; however, there was not strong evidence for differences within each class. This finding might reflect limits of the DAP-sequencing method, such as that caused by the required clustering of many promoters according to investigators’ hypotheses about functional features, or the fact that transcription factor binding and activation are frequently decoupled (Para et al., 2014). To complement past studies, we tested the activation profiles of Class A ARFs (specifically the AtARF5/ZmARF4/ZmARF29 clade and the AtARF19/ZmARF27 clade) from Arabidopsis (Arabidopsis thaliana) and maize (Zea mays) on standardized synthetic promoter variants in yeast (Saccharomyces cerevisiae; Fig. 1A; Pierre-Jerome et al., 2014). Promoter variants were inserted into the pIAA19 promoter with mutated AuxREs. None of the ARFs tested can activate transcription to any appreciable extent on this promoter (Supplemental Fig. S1). Through these analyses, we discovered several ARF-activated promoter design rules. First, activation strength was directly proportional to Auxin Response Element (AuxRE) copy number (Fig. 1B). Second, ARFs activated more strongly on two AuxREs facing toward each other rather than away from each other (Fig. 1, C and D). Only AtARF19 showed appreciable activation on two AuxREs facing away from each other. Third, orientation relative to the transcription start site (TSS) mattered. AtARF19 activated slightly more strongly on two AuxREs facing toward the TSS as opposed to away from the TSS (Fig. 1E). No other tested ARFs activated on two AuxREs facing away from the TSS, though ZmARF27 and ZmARF29 activated on two AuxREs facing toward the TSS (Fig. 1F). These design rules suggest that ARFs exhibit conserved preferences for cis-element orientation and number. Figure 1. Open in new tabDownload slide Arabidopsis and maize ARFs share promoter preferences. A, Schematic of yeast engineered to constitutively express ARF proteins and promoter variants. The TSS is to the right and arrowheads indicate the orientation of the AuxRE, starting with 5′-TGTC-3′. Fluorescence was measured by flow cytometry with the results depicted as median values and 95% confidence intervals. Twenty-thousand events (cells) were measured for each replicate. B, AtARF19 and AtARF5 show strong activation on promoters with four AuxREs (five-bp spacer of the sequence CCTTT). C, AtARF19 and AtARF5 show stronger activity on promoters with two AuxREs facing toward each other rather than away from each other (seven-bp spacer of the sequence CCAAAGG). D, ZmARF4, ZmARF27, and ZmARF29 show stronger activity on promoters with two AuxREs facing toward each other rather than away from each other (seven-bp spacer of the sequence CCAAAGG). E, AtARF19 and AtARF5 show stronger activity on promoters where the two AuxREs face toward rather than away from the TSS (five-bp spacer of the sequence CCTTT). F, ZmARF4, ZmARF27, and ZmARF29 show stronger activity on promoters where the two AuxREs face toward rather than away from the TSS (five-bp spacer of the sequence CCTTT). Figure 1. Open in new tabDownload slide Arabidopsis and maize ARFs share promoter preferences. A, Schematic of yeast engineered to constitutively express ARF proteins and promoter variants. The TSS is to the right and arrowheads indicate the orientation of the AuxRE, starting with 5′-TGTC-3′. Fluorescence was measured by flow cytometry with the results depicted as median values and 95% confidence intervals. Twenty-thousand events (cells) were measured for each replicate. B, AtARF19 and AtARF5 show strong activation on promoters with four AuxREs (five-bp spacer of the sequence CCTTT). C, AtARF19 and AtARF5 show stronger activity on promoters with two AuxREs facing toward each other rather than away from each other (seven-bp spacer of the sequence CCAAAGG). D, ZmARF4, ZmARF27, and ZmARF29 show stronger activity on promoters with two AuxREs facing toward each other rather than away from each other (seven-bp spacer of the sequence CCAAAGG). E, AtARF19 and AtARF5 show stronger activity on promoters where the two AuxREs face toward rather than away from the TSS (five-bp spacer of the sequence CCTTT). F, ZmARF4, ZmARF27, and ZmARF29 show stronger activity on promoters where the two AuxREs face toward rather than away from the TSS (five-bp spacer of the sequence CCTTT). In addition to number and orientation, the sequence of AuxREs impacted the magnitude of ARF-mediated activation. The first described AuxRE was the six-mer TGTCTC (Ballas et al., 1993); however, later work revealed flexibility in the fifth and sixth position. AtARF1 and AtARF5 bind more strongly to the AuxRE TGTCGG than to TGTCTC (Boer et al., 2014). Our assays reveal that activation strength follows this binding preference, with each ARF tested activating more strongly on two AuxREs facing toward each other of the sequence TGTCGG (Fig. 2A). The nearly 9-fold increase in AtARF5 activity was particularly dramatic, and is of relevance for the design and interpretation of auxin reporters. DR5v2, which uses TGTCGG (Liao et al., 2015), may over-report responses driven by AtARF5 relative to other ARFs. Figure 2. Open in new tabDownload slide The AuxRE sequence TGTCGG strengthens ARF activity and allows for AtARF19 activity on a single cis-element. Fluorescence was measured by flow cytometry with the results depicted as median values and 95% confidence intervals. Twenty-thousand events (cells) were measured for each replicate. A, All ARFs tested activate more strongly on two AuxREs facing each other of the cis-element sequence TGTCTC/GAGACA when compared to two AuxREs facing each other of the cis-element sequence TGTCGG/CCGACA. B, Only AtARF19 of the ARFs tested can induce transcription on a promoter with one AuxRE of the sequence 5′-TGTCGG-3′ (the no-ARF control data point is directly underneath the ZmARF4 data point). C, Alignment of the DNA-binding domains and DDs of AtARF19 and ZmARF27 with relevant mutations highlighted. D, Structure of ARF5 DNA-binding domain with mutated residues highlighted. E, AtARF19 must dimerize for full activity, even for a promoter with a single AuxRE. The KO triple mutation (K962A; D1012A; D1016A) disrupts dimerization in the Phox and Bem1 domain. The A250N and G247I mutations disrupt dimerization at the DD, adjacent to the DNA-binding domain. The H138A mutation disrupts the DNA-binding domain itself. F, An N256A mutation in AtARF19 causes a total loss of activity on a promoter with one AuxRE (5′-TGTCGG-3′), whereas activity on two AuxREs was largely intact. Figure 2. Open in new tabDownload slide The AuxRE sequence TGTCGG strengthens ARF activity and allows for AtARF19 activity on a single cis-element. Fluorescence was measured by flow cytometry with the results depicted as median values and 95% confidence intervals. Twenty-thousand events (cells) were measured for each replicate. A, All ARFs tested activate more strongly on two AuxREs facing each other of the cis-element sequence TGTCTC/GAGACA when compared to two AuxREs facing each other of the cis-element sequence TGTCGG/CCGACA. B, Only AtARF19 of the ARFs tested can induce transcription on a promoter with one AuxRE of the sequence 5′-TGTCGG-3′ (the no-ARF control data point is directly underneath the ZmARF4 data point). C, Alignment of the DNA-binding domains and DDs of AtARF19 and ZmARF27 with relevant mutations highlighted. D, Structure of ARF5 DNA-binding domain with mutated residues highlighted. E, AtARF19 must dimerize for full activity, even for a promoter with a single AuxRE. The KO triple mutation (K962A; D1012A; D1016A) disrupts dimerization in the Phox and Bem1 domain. The A250N and G247I mutations disrupt dimerization at the DD, adjacent to the DNA-binding domain. The H138A mutation disrupts the DNA-binding domain itself. F, An N256A mutation in AtARF19 causes a total loss of activity on a promoter with one AuxRE (5′-TGTCGG-3′), whereas activity on two AuxREs was largely intact. To define a minimal auxin-responsive promoter, we tested whether any of the ARFs could activate on a single AuxRE of the sequence TGTCGG, and found that only AtARF19 was able to activate on this single AuxRE (Fig. 2B). In fact, AtARF19 activated almost as strongly on a promoter with a single AuxRE of this sequence as that observed on promoters with two AuxREs. ARFs are thought to require dimerization through their N-terminal dimerization domain (DD) to bind DNA (Boer et al., 2014). We tested whether dimerization through either the DD or the C-terminal Phox and Bem1 domain (Korasick et al., 2014; Nanao et al., 2014) impacted AtARF19 activation on a promoter with a single AuxRE (Fig. 2, C and D), as mutations in either of these domains reduce AtARF19 activity on promoters with multiple AuxREs (Pierre-Jerome et al., 2016). The DD mutations caused a severe loss of activity comparable to a mutation in the DNA-binding domain itself (Fig. 2E). The effect of the PB1 mutations was less severe on promoters with two AuxREs, suggesting a compensatory effect of multiple binding sites. The mechanism through which an ARF dimer binds to a single-AuxRE promoter is unknown. One possibility is that a single ARF-AuxRE contact provides sufficient stability to allow activation and the other ARF in the dimer forms transient interactions with DNA sequences that serve as low-affinity binding sites. Alternatively, the two ARFs within a dimer pair could “trade places” on the single AuxRE, providing sufficient occupancy time to allow for activation. Sequence alignments revealed a difference within the DD of AtARF19 and its maize homolog (Fig. 2, C and D). To test if this single residue difference, so close to the contact residues within the DD (Fig. 2D), could explain AtARF19’s unique ability to activate on a single AuxRE, we mutated the AtARF19 DD to the ZmARF27 sequence (N256A). This mutation abolished AtARF19 activity on a single AuxRE, whereas activity on two AuxREs was essentially unchanged (Fig. 2F). The polarity of the Asn may help stabilize the dimeric form of AtARF19, leading to higher transcriptional activation and expanding the range of promoters it can activate. Whereas N256 is necessary for AtARF19’s ability to activate on promoters with a single AuxRE, it is not sufficient. AtARF7, which shares the same Asn residue in its DD, cannot activate on a single AuxRE (Supplemental Fig. S2), suggesting that interdomain interactions may be critical for overall ARF function. It has been widely speculated that specificity in ARF-promoter interactions is responsible for the diversity of auxin responses. Our results suggest that this model is unlikely to be true, and suggests that factors outside the core auxin response machinery may provide that function. Closely spaced AuxREs are found only rarely in the Arabidopsis genome (Grigolon et al., 2018), and frequently are neither of the ideal sequence nor in the ideal orientation relative to the TSS. The rarity of “ideal” promoters may allow for integration of signals from multiple pathways, a hypothesis supported by the enrichment of transcription factor binding sites for other proteins in auxin-responsive promoters (Berendzen et al., 2012; Mironova et al., 2014; Cherenkov et al., 2018). Future efforts that combine synthetic and native approaches will be needed to pinpoint the combination of factors that make up the “auxin code,” as well as to make it possible to retrace the evolutionary path that connected novel auxin response modules to diversity in plant form and function. Supplemental Data The following supplemental materials are available. Supplemental Figure S1. Arabidopsis and maize ARFs do not activate on mpIAA19. Supplemental Figure S2. 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Proc Natl Acad Sci USA 113 : 11354 – 11359 Google Scholar Crossref Search ADS PubMed WorldCat Wilmoth JC , Wang S, Tiwari SB, Joshi AD, Hagen G, Guilfoyle TJ, Alonso JM, Ecker JR, Reed JW ( 2005 ) NPH4/ARF7 and ARF19 promote leaf expansion and auxin-induced lateral root formation . Plant J 43 : 118 – 130 Google Scholar Crossref Search ADS PubMed WorldCat Author notes 1 This work was supported by the National Science Foundation (MCB-1411949 to J.L.N., IOS-1609014 to M.T.-T., and DGE-1256082 to A.L.); the Department of Health and Human Services at the National Institutes of Health (R01-GM107084 to J.L.N.); and the Howard Hughes Medical Institute (Faculty Scholar Award to J.L.N.). [CC-BY] Article free via Creative Commons CC-BY 4.0 license. 3 Senior author. The author responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (www.plantphysiol.org) is: Jennifer L. Nemhauser ([email protected]). www.plantphysiol.org/cgi/doi/10.1104/pp.19.01474 © 2020 The authors. All Rights Reserved. © The Author(s) 2020. Published by Oxford University Press on behalf of American Society of Plant Biologists. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Lanctot, Amy; Taylor-Teeples, Mallorie; Oki, Erika A.; Nemhauser, Jennifer L.

doi: 10.1104/pp.19.01474pmid: 31937684

Tal, Lior; Gil, M. Ximena Anleu; Guercio, Angelica M.; Shabek, Nitzan

doi: 10.1104/pp.19.01282pmid: 31919187

Abstract Hormonal cues regulate many aspects of plant growth and development, facilitating the plant’s ability to systemically respond to environmental changes. Elucidating the molecular mechanisms governing these signaling pathways is crucial to understanding how plants function. Structural and functional biology methods have been essential in decoding plant genetic findings and revealing precise molecular actions at the protein level. Past studies of plant hormone signaling have uncovered mechanisms that involve highly coordinated protein turnover to elicit immediate cellular responses. Many phytohormone signaling pathways rely on the ubiquitin (Ub) proteasome system, specifically E3 Ub ligases, for perception and initiation of signaling transduction. In this review, we highlight structural aspects of plant hormone-sensing mechanisms by Ub ligases and discuss our current understanding of the emerging field of strigolactone signaling. Historically, the study of plants has greatly advanced human knowledge. Numerous scientific landmarks were first discovered in plants including the laws of genetic heredity, cytogenetics, RNA interference, transposable elements, and the identification of the first virus (Mendel, 1865; Vines, 1880; Beijerinck, 1898; McClintock, 1984; Napoli et al., 1990; van der Krol et al., 1990) Similarly, proteins extracted from plant tissues laid the foundations of protein crystallography. In 1926, James Batcheller Sumner used Jack beans (Canavalia ensiformis) to isolate and crystalize, for the first time, the protein Urease (Sumner, 1926). In addition to revealing the first protein crystals, Sumner’s work also provided the very first evidence that enzymes are proteins. In the era of x-ray crystallography and high-resolution single particle electron microscopy, determining three-dimensional protein structures in atomic detail has become the ultimate tool to decrypt the molecular mechanism of biological pathways. Despite the advances made in structural biology methodologies, the percentages of plant protein structures deposited in Protein Data Bank (PDB; Berman et al., 2000) have remained remarkably low compared with other kingdoms of life . Nevertheless, the past decade has witnessed groundbreaking structure-function studies in plants. These studies have had a significant impact on our understanding of fundamental biological processes, including photomorphogenesis, immune responses, and, in particular, phytohormone signaling pathways. Open in new tabDownload slide Open in new tabDownload slide Plants maintain the ability to respond to environmental changes by altering growth patterns and varying developmental outcomes. This plasticity is attributed to the ability of plants to translate the environmental input into a systemic signal using a diverse range of molecular instruments, orchestrated by phytohormones. Many important genetic studies have identified the distinct key players of hormonal signaling cascades. The recent integration of structural biology with plant genetics has uncovered molecular mechanisms through which a small molecule can facilitate protein-protein interactions and trigger the transduction of a signal into a developmental outcome. Phytohormones comprise a set of structurally unrelated small organic compounds. Notably, most phytohormone signaling pathways are tightly regulated by a highly coordinated intracellular protein degradation machine known as the ubiquitin-proteasome system (UPS; see Box 1). The specificity of UPS is conferred by the action of a family of E3 ubiquitin ligase enzymes that target specific proteins for destruction in a timely manner (Hershko and Ciechanover, 1998; Zheng and Shabek, 2017). Plants have used this machinery multiple times across evolution to achieve time-dependent activation of a signaling pathway upon phytohormone perception. In this review, we focus on and outline the structural aspects of plant hormone perception by the UPS, and detail the contribution of these findings to our understanding of signaling at the molecular level. We also discuss the current view and recent advances in the emerging field of strigolactone (SL) signaling. Open in new tabDownload slide Open in new tabDownload slide PERCEPTION AND SIGNALING BY UBIQUITIN LIGASES The first line of phytohormone perception involves distinct intracellular protein receptors that evolved to sense and respond to extremely low concentrations of these naturally occurring chemical signals. By leveraging the structurally diverse low molecular weight of these small molecules, phytohormones were proposed to facilitate selective protein-protein interaction and subsequently initiate a sequence of signaling cascades. Notably, Cullin-RING ligases, one of the prevalent E3 ligase superfamilies, were found to function as sensing centers in plant hormone perception and signaling (Vierstra, 2009; Shabek and Zheng, 2014). Cullin1, one of the CUL1–4 subtypes, serves as a large scaffold module with a C-terminal portion that interacts with the E2-recruiting RING domain (RBX1) and an N-terminal portion that binds the interchangeable substrate-receptor F-box protein via SKP1/ASK1 to form the functional ligase multisubunit SCF (Skp1-Cullin1-F-box; see Box 1 and Fig. 1). To better illustrate the molecular basis of phytohormone signaling cascade, we divided the receptors into two main modes of actions: direct interaction enhancers (molecular glues) and allosteric effectors. The perception mechanism of auxin and jasmonates (JAs) operates as molecular glue as the presence of these phytohormones enhances the interactions between the F-box receptors and their target proteins. On the other hand, GAs and SLs act as allosteric effectors by inducing conformational changes in their receptors to regulate downstream interactions with F-box proteins. This review focuses on the contribution of E3 ligases as direct or allosteric receptors; however, a dominant role of the UPS in downstream parts of the signaling cascade was documented for several other hormones, such as ethylene, cytokinin (Kim et al., 2013; Lee and Seo, 2015; Chen et al., 2018), and multiple components of abscisic acid signaling, as reviewed in Yu et al. (2016). Figure 1. Open in new tabDownload slide Structural models of direct phytohormone perception and target recognition by E3 Ub ligase receptors. SCFTIR1 (A) and SCFCOI1 (B) mediate AUX/IAA and JAZ ubiquitination and degradation, respectively. Auxin and Ja-Ile (Jasmonic Acid – Ile) are directly perceived by F-box receptors (TIR1 and COI1, respectively), and this results in an altered interface that recruits substrate for ubiquitination and degradation. In the SCF (SKP1-CUL1-F-box) complex, Cullin1 serves as a scaffold that binds RBX1 (RING protein, required for E2-Ub recruitment) via its C terminus and ASK1/SKP1 (F-box adaptor protein) via its N terminus. In (i), molecular surface of TIR1 (PDB: 2P1Q) and COI1 (PDB: 3OGL) crystal structures are modeled with CUL1-RBX1 (PDB: 1LDK). In (ii), phytohormone recognition interface between F-box LRR and the target substrate recognition element (degron) is shown. Detailed amino acid side chain interactions with auxin (A) and JA (B) are shown in the small framed windows. In (iii), a model of phytohormone signaling mechanism is shown. All colored texts are consistent with colored structural elements. Ubiquitination is denoted U. Figure 1. Open in new tabDownload slide Structural models of direct phytohormone perception and target recognition by E3 Ub ligase receptors. SCFTIR1 (A) and SCFCOI1 (B) mediate AUX/IAA and JAZ ubiquitination and degradation, respectively. Auxin and Ja-Ile (Jasmonic Acid – Ile) are directly perceived by F-box receptors (TIR1 and COI1, respectively), and this results in an altered interface that recruits substrate for ubiquitination and degradation. In the SCF (SKP1-CUL1-F-box) complex, Cullin1 serves as a scaffold that binds RBX1 (RING protein, required for E2-Ub recruitment) via its C terminus and ASK1/SKP1 (F-box adaptor protein) via its N terminus. In (i), molecular surface of TIR1 (PDB: 2P1Q) and COI1 (PDB: 3OGL) crystal structures are modeled with CUL1-RBX1 (PDB: 1LDK). In (ii), phytohormone recognition interface between F-box LRR and the target substrate recognition element (degron) is shown. Detailed amino acid side chain interactions with auxin (A) and JA (B) are shown in the small framed windows. In (iii), a model of phytohormone signaling mechanism is shown. All colored texts are consistent with colored structural elements. Ubiquitination is denoted U. AUXINS AND JAS AS “MOLECULAR GLUES” Auxin and JAs were the first hormones shown to be perceived by the F-box proteins TRANSPORT INHIBITOR RESPONSE 1 (TIR1; Ruegger et al., 1998; Dharmasiri et al., 2005; Kepinski and Leyser, 2005) and CORONATINE INSENSITIVE1 (COI1; Feys et al., 1994; Xie et al., 1998; Katsir et al., 2008), respectively. Extensive genetic and biochemical studies before any structural insight on the pathways showed that auxin and JAs induce the rapid degradation of distinct families of corepressors Auxin/INDOLE-3-ACETIC ACID (Aux/IAA; Abel et al., 1994; Gray et al., 2001; Tiwari et al., 2001) and JASMONATE ZIM DOMAIN (JAZ; Chini et al., 2007; Yan et al., 2007), which is followed by subsequent transcriptional activation of hormone-responsive genes. The groundbreaking revelation of TIR1-Aux/IAA (Tan et al., 2007) and COI1-JAZ (Sheard et al., 2010) crystal structures illuminated the molecular basis for the perception of these phytohormones. These structural studies uncovered a new mechanism of ligand perception in which hormones act as “molecular glue” in macromolecular assembly. In the case of auxin, auxin docking to the bottom of TIR1 (via a side chain carboxyl group and an indole ring) creates a modified surface that stabilizes its interaction with Aux/IAAs, leading to their polyubiquitination and degradation. TIR1 and COI1 are structurally similar to horseshoe-shaped Leu Rich Repeat (LRR) domains followed by F-box domain bound to ASK1 adaptor (Fig. 1). The top surfaces of the TIR1- and COI1-LRR domains form a shallow pocket that binds both the hormone and the target substrate (Aux/IAA or JAZ). A short recognition motif (degron) within Aux/IAAs directly engages with auxin-loaded TIR1 and sandwiches auxin in the middle (Fig. 1A). Similarly, JAZ degrons interact with COI1 to ensure high-affinity hormone binding. The JAZ degron covers the opening where JA-Ile binds and traps the hormone in the pocket (Fig. 1B). Interestingly, both structures revealed the presence of secondary small molecule metabolites at the hormone perception site, inositol hexakisphosphate (InsP6) in TIR1 and inositol pentakisphosphate (InspP5) in COI1. These cofactors directly interact with the hormone-binding pocket and potentiate the hormone-receptor-substrate interaction. The structural studies of the auxin and JA pathways were instrumental in improving our understanding of hormonal cues and transcriptional regulation. Aux/IAAs and JAZs participate in transcriptional repressive complexes containing transcription factors like AUXIN RESPONSE FACTOR (ARFs) for auxin and MYC for JA, adaptor proteins like NOVEL INTERACTOR OF JAZ (NINJA) for JAs, and corepressors like TOPLESS (TPL) for both phytohormones (Lorenzo et al., 2004; Szemenyei et al., 2008; Pauwels et al., 2010). Crystal data of the NINJA-TPL interaction uncovered the molecular basis of protein interactions with TPL through their ethylene response factor–associated amphiphilic repression (EAR) motifs (Ke et al., 2015). Crystallographic data of ARFs alone (Boer et al., 2014) or complexed with Aux/IAAs (Nanao et al., 2014) revealed the structural foundations of oligomerization of auxin transcriptional repressors, whereas the structure of MYC3 (Zhang et al., 2015) was the first illustration of noncomplexed MYC transcription activation domain. These are selected examples that illustrate the value of adding crystallographic data to the fields of plant development and physiology. Efforts to understand transcriptional repressive complexes at the biochemical and structural level of other hormones are necessary to gain a full appreciation of the complexity of hormone-dependent transcriptional regulation. GAs and SLs as allosteric activators Unlike TIR1 and COI1, the GA and SL receptors are not F-box proteins themselves. The GA receptor GIBBERELLIN INSENSITIVE DWARF 1 (GID1) and the SL receptor DWARF 14 (D14) are α/β hydrolases that associate with F-box proteins in a hormone-dependent manner to recognize substrate proteins for ubiquitination and degradation. In contrast with the “molecular glue” mechanism, GAs and SLs induce conformational changes in their receptors that enable them to interact with their respective F-box proteins (Fig. 2). GID1 is a soluble protein (Ueguchi-Tanaka et al., 2005) that has structural similarity to hormone-sensitive lipases involved in lipid metabolism in animals (Yeaman, 2004). Perception of GA by GID1 induces conformational changes in the enzyme that enable it to interact with the SCF-type E3 Ub ligase AtSLEEPY1 (SLY1)/AtSNEEZY (SNZ)/OsGID2 (SCFGID2/SLY1) to ubiquitinate and degrade DELLA transcriptional regulators, including GIBBERELLIN INSENSITIVE (GAI1; Peng et al., 1997; Fu et al., 2002; McGinnis et al., 2003; Sasaki et al., 2003; Ueguchi-Tanaka et al., 2007). Figure 2. Open in new tabDownload slide Structural models of allosteric regulation of phytohormone perception and signaling by E3 Ub ligases. A, Crystal structure of GA perception complex (based on PDB: 2ZSI) contains GA3, GID1A, and the DELLA domain of GAI. In (i), molecular surface of GID1A N-terminal extension (N-Ex, labeled in violet) and its core (labeled in blue) are shown. Helices of GAI DELLA (labeled green) are represented as cylinders. In (ii), there is recognition interface between GID1-GA and DELLA, shown in detail by ribbon representation. The inset represents detailed amino acid side chain interfaces. In (iii), a model for GA perception and signaling is shown. GA binding induces a conformational change in the N-Ex of GID1 and promotes an interaction with the DELLA domain. Subsequently, GID1-GA-DELLA can be recognized and ubiquitinated (U) by SCFSLY. B, (i) and (ii), molecular surface representation of ASK1-D3 complex and CTH (light blue) dislodged. D14, the SL receptor (labeled in green; SL in magenta), is bound to D3-CTH (light blue) in an open conformation and can perceive SL. Crystals structures are modified from Shabek et al. (2018; based on PDB: 6BRO and 6BRT). In (iii) and (iv), molecular surface representation of ASK1-D3-D14 complex in a closed conformation (modified from Yao et al. (2016); based on PDB: 5HZG). C, Model of SL signaling. In (i), D3/MAX2 binds D14, the SL receptor, via D3′s CTH. In (ii), this interaction results in an allosteric inhibition of SL hydrolysis, allowing sufficient time to recruit and ubiquitinate (U) D53/SMXL’s transcriptional repressors. In (iii), targeting of D53 through SCFD3 triggers a conformational change in D3 and D14 that results in SL hydrolysis by D14 and a butenolide-bound intermediate (CLIM, small magenta triangle). D14 is subsequently ubiquitinated by D3 and recycled and/or degraded to reset the signal. Figure 2. Open in new tabDownload slide Structural models of allosteric regulation of phytohormone perception and signaling by E3 Ub ligases. A, Crystal structure of GA perception complex (based on PDB: 2ZSI) contains GA3, GID1A, and the DELLA domain of GAI. In (i), molecular surface of GID1A N-terminal extension (N-Ex, labeled in violet) and its core (labeled in blue) are shown. Helices of GAI DELLA (labeled green) are represented as cylinders. In (ii), there is recognition interface between GID1-GA and DELLA, shown in detail by ribbon representation. The inset represents detailed amino acid side chain interfaces. In (iii), a model for GA perception and signaling is shown. GA binding induces a conformational change in the N-Ex of GID1 and promotes an interaction with the DELLA domain. Subsequently, GID1-GA-DELLA can be recognized and ubiquitinated (U) by SCFSLY. B, (i) and (ii), molecular surface representation of ASK1-D3 complex and CTH (light blue) dislodged. D14, the SL receptor (labeled in green; SL in magenta), is bound to D3-CTH (light blue) in an open conformation and can perceive SL. Crystals structures are modified from Shabek et al. (2018; based on PDB: 6BRO and 6BRT). In (iii) and (iv), molecular surface representation of ASK1-D3-D14 complex in a closed conformation (modified from Yao et al. (2016); based on PDB: 5HZG). C, Model of SL signaling. In (i), D3/MAX2 binds D14, the SL receptor, via D3′s CTH. In (ii), this interaction results in an allosteric inhibition of SL hydrolysis, allowing sufficient time to recruit and ubiquitinate (U) D53/SMXL’s transcriptional repressors. In (iii), targeting of D53 through SCFD3 triggers a conformational change in D3 and D14 that results in SL hydrolysis by D14 and a butenolide-bound intermediate (CLIM, small magenta triangle). D14 is subsequently ubiquitinated by D3 and recycled and/or degraded to reset the signal. The mechanism by which GA is recognized by GID1 was elucidated by the crystal structures of GA-bound GID1 in both free and DELLA-associated forms (Murase et al., 2008; Shimada et al., 2008). GAI1 is a monomeric protein composed of one α/β core hydrolase (albeit with a nonfunctional catalytic triad; Ueguchi-Tanaka et al., 2005) and a unique N-terminal extension that folds back over the GA-bound pocket upon hormone perception and covers it like a lid (Fig. 2A). This process creates binding surfaces for the N-terminal DELLA domain of GAI1. Binding of this region to GID1 induces its coil-to-helix conformational transition, which in turn affects the structure of the C-terminal GRAS domain of the same protein. Mediated by the GRAS domain, the GID1-GA-DELLA complex is then recognized by the SCFGID2/SLY1 for ubiquitination and degradation of the DELLAs by the UPS. The structure of a GRAS domain has been recently solved in the non-DELLA protein SCARECROW-LIKE 7 (SCL7; Li et al., 2016). However, determining the structure of the GID1-GA-DELLA complex with SCFGID2/SLY1 will further our understanding of the GA signaling core regulatory mechanism. The most recently identified phytohormone, SL, represents yet another new perception and signaling paradigm wherein both the F-box protein, namely MORE AXILLARY BRANCHES2 / DWARF3 (MAX2/D3), and the SL receptor α/β-hydrolase, namely, have multiple functional states. Similar to GA perception, SL does not function as molecular glue in the interface between the receptor and the E3 ligase. Unlike GID1, the D14 is an active hydrolase that slowly metabolizes SL into nonbioactive products. Here, D14 forms a SL-dependent complex with SCF-MAX2/D3 and recruits DWARF53 (D53; rice [Oryza sativa]) or SUPPRESSOR OF MAX2 LIKE (SMXL6/7/8; Arabidopsis [Arabidopsis thaliana]) for ubiquitination and rapid proteasomal degradation. The dynamic state of SL perception, hydrolysis, and signaling is biologically intriguing yet perplexing. The following part of this review will discuss our current understanding of SL perception and regulation. SL PERCEPTION BY THE UPS AND DOWNSTREAM SIGNALING SLs were first identified as germination stimulants of the parasitic witchweed Striga hermonthica, following their isolation from cotton (Gossypium hirsutum) root exudates in 1966 (Cook et al., 1966). Since 1966, researchers have characterized a variety of SLs as well as a diversity of functions of the SL molecule(s). SLs function exogenously to initiate symbiosis with mycorrhizal fungi and incidentally stimulate germination of parasitic plants (Akiyama et al., 2005). Whereas SLs function endogenously and regulate many aspects of growth and development, they are notoriously known to inhibit shoot branching (Gomez-Roldan et al., 2008; Umehara et al., 2008). Before the SL receptor was identified, MAX2 was first recognized as a protein involved in SL-related pathways (Stirnberg et al., 2002; Stirnberg et al., 2007; Gomez-Roldan et al., 2008). Mutant max2 plants presented phenotypes similar to SL synthesis mutants (Stirnberg et al., 2002; Booker et al., 2005; Ishikawa et al., 2005; Gomez-Roldan et al., 2008); however, unlike these mutants, max2 phenotypes could not be rescued with SL treatment, pointing to MAX2 involvement in SL signaling (Umehara et al., 2008). MAX2 encodes an F-box E3 ubiquitin ligase that targets its substrates for selective protein degradation. Thus, at the birth of the field it was apparent that like auxin, JA, salicylic acid, and GA signaling pathways, the SL signaling cascade was dependent on regulated turnover via the UPS. Later, the SL receptor protein was first identified via its mutant characterized by an increased shoot branching phenotype (Arite et al., 2009). Multiple groups provided evidence that an α/β hydrolase such as D14 was responsible, and in fact later showed that D14 is the receptor of SL (Arite et al., 2009; Hamiaux et al., 2012; Waters et al., 2012; de Saint Germain et al., 2016). The SL receptor is remarkable because it serves as both a receptor as well as an enzyme, capable of hydrolyzing its ligand SL (Hamiaux et al., 2012; Waters et al., 2012; Zhao et al., 2013; Abe et al., 2014; Waters et al., 2015; de Saint Germain et al., 2016; Shahul Hameed et al., 2018; Yao et al., 2018; Bürger et al., 2019). The sought-after degradation targets of the MAX2-D14 complex were characterized in 2013 using the rice mutant d53 that shows increased branching and SL-insensitivity phenotypes. D53 encodes a protein that shares a similar secondary structure composition to proteins of the class I Clp ATPase family (Jiang et al., 2013; Zhou et al., 2013). D53/SMXLs contain a transcriptional repressor EAR motif and are rapidly degraded in response to D14-MAX2-dependent SL treatment (Zhou et al., 2013; Soundappan et al., 2015; Wang et al., 2015; Liang et al., 2016). Unlike in other phytohormone signaling cascades, the exact function and the specific transcriptional targets of D53/SMXLs remain largely unknown (Song et al., 2017). SL perception and hydrolysis by D14 Structural biology has become a promising tool in understanding the function, specificity, and complexity of the D14-SL perception mechanism. The crystal structures of D14 have been determined for Arabidopsis, rice (Kagiyama et al., 2013; Zhao et al., 2013), striga (Xu et al., 2018), and petunia (Petunia hybrida; Hamiaux et al., 2012). These structures reveal a common α/β hydrolase fold with a deep pocket that is formed by a V-shaped lid composed of four α-helices. The D14 pocket contains a canonical Ser catalytic triad that is conserved across plant species, indicating that the protein hydrolase activity was maintained throughout evolution (Bythell-Douglas et al., 2017). Notably, the pocket is widely open to solvent, and several crystal structures have claimed to capture synthetic SL analogs or byproducts bound to D14 (Jiang et al., 2013; Nakamura et al., 2013; Zhao et al., 2013; Zhao et al., 2015; Takeuchi et al., 2018). Whereas it has been biochemically demonstrated that the binding pocket can accommodate SL for hydrolysis, it is less clear whether any of the D14 structures are able to capture the ligand at atomic resolution. Because of the low occupancy and poor electron density of SL analogs in all D14 crystal structures, the precise position and topography of SL has remained considerably elusive (Carlsson et al., 2018). One of the major questions in the SL field is centered on SL hydrolysis and its necessity to propagate SL signaling. Much of the consensus was driven by the idea that hydrolysis of SL conferred a conformational change in D14, thus providing an interfacing ability with SCF-MAX2 Ub ligase (de Saint Germain et al., 2016; Yao et al., 2016). However, the requirement of hydrolysis was challenged by a recent study showing that D14 catalysis mutants are able to bind SL, but not hydrolyze it, and rescue the d14 mutant phenotype in a SL-dependent manner. This implies that SL binding (not hydrolysis) is necessary for initiating the signaling cascade (Seto et al., 2019). Additionally, the distinct states of intact SL binding and SL hydrolysis may confer different signals. In this model, one state is important for D14-MAX2 to create an interface for SMXLs, and another for the release or degradation of D14 and/or deactivation of the SL molecule. Nonetheless, in all these cases, it is the Ub ligase MAX2 that directs the rate of SL hydrolysis, the interactions, and the proteasomal degradation of D14 and SMXLs. SL regulation by the Ub ligase SCF-MAX2/D3 Protein structures containing the complex of D14-D3 (D3, rice ortholog of MAX2) indicate an even more intriguing level of complexity and regulation at the level of the Ub ligase. It was shown that D14 undergoes a great conformational change when complexed with D3, presumably after SL hydrolysis (Yao et al., 2016). This finding was strongly supported by the identification of a SL-hydrolysis covalently linked intermediate molecule (CLIM), and by the fact that D14 is a single turnover enzyme (or very slowly releases SL products in vitro; de Saint Germain et al., 2016; Yao et al., 2016). Given that D14 is also targeted for degradation by MAX2 (Chevalier et al., 2014), it is unclear whether the D14CLIM-D3 complex recapitulates the effective interface to recruit SMXLs or simply targets the receptor to reset signaling. A recent study reported another mode of action that is centered around the conformational state of the Ub ligase (Shabek et al., 2018). It has been shown that MAX2/D3 exists in multiple functional states highlighted by a flexible, highly conserved C-terminal alpha helix domain (CTH). The CTH, which is the last LRR repeat within the horseshoe structure, can be either open (dislodged) or closed (engaged). The dislodged D3-CTH can directly bind D14-SL, and this interaction results in allosteric inhibition of SL hydrolysis (Fig. 2B). It was also proposed that the dislodged form provides an interface to enable the recruitment of D53/SMXLs and their subsequent ubiquitination and degradation (Shabek et al., 2018). Before D53/SMXLs are released to the proteasome, the transient interaction with D3 alters D14 inhibition and slowly restores SL hydrolysis. The restored activity can successively reset the SL signal by both depleting SL and degrading the D14 receptor until the next environmental cue. Taken together, the mode of perception and signaling cascade of SL is likely dynamic and complex and may differ molecularly from other characterized phytohormone signaling pathways. Open in new tabDownload slide Open in new tabDownload slide CONCLUDING REMARKS The study of phytohormone perception and signaling cascades illustrates the importance of complementary genetic and structural biology methods. Integration of data from both disciplines overcomes their individual limitations and leads to a holistic understanding of molecular processes. In this review, we described various structural studies outlining how plants utilize the UPS to perceive hormonal triggers and activate signaling cascades. Hormone perception followed by protein complex formation is a dynamic, multifaceted process, and an x-ray crystallography approach may recapitulate a single energetically favored state of the protein machinery. Thus, comprehensive understanding of the molecular action of Ub ligase complexes in plant hormone biology remains a great challenge that is technically difficult to recapitulate at atomic resolution. For example, considering the gaseous phytohormone ethylene, the structure function of its perception mechanism is currently unresolved, although its signaling components are well known. The contribution of structural biology to plant biology has been immense and likely to provide answers to many unresolved questions (see Outstanding Questions). Whereas x-ray crystallography has remained the favorable approach to determine Ub ligase function in hormone signaling, this method relies heavily on minimum protein flexibility and maximum ability to be organized in a rigid and specific pattern. This notion can explain why most published structures were recapitulated using only portion of the complex components (AUX/IAA, JAZ, SLY). The emerging method of single particle cryo-electron microscopy holds promise to resolve the long-standing challenges of dynamic full-length complete protein complexes in plant hormone biology. ACKNOWLEDGMENTS We apologize to those colleagues whose work was not cited due to space constraints. LITERATURE CITED Abe S , Sado A, Tanaka K, Kisugi T, Asami K, Ota S, Kim HI, Yoneyama K, Xie X, Ohnishi T, et al. 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Nature 504 : 406 – 410 Google Scholar Crossref Search ADS PubMed WorldCat Author notes 1 This work was supported by United States - Israel Binational Agricultural Research and Development Fund (BARD; Vaadia-BARD Postdoctoral Fellowship Award FI-559-2017 to L.T) and University of California Davis College of Biological Sciences Start-Up Funds to N.S. [OPEN] Articles can be viewed without a subscription. 2 Senior author. All authors participated in writing the paper. www.plantphysiol.org/cgi/doi/10.1104/pp.19.01282 © 2020 American Society of Plant Biologists. All Rights Reserved. © The Author(s) 2020. Published by Oxford University Press on behalf of American Society of Plant Biologists. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Tal, Lior; Gil, M. Ximena Anleu; Guercio, Angelica M.; Shabek, Nitzan

doi: 10.1104/pp.19.01282pmid: 31919187

Li, Qi; Wang, Chenggang; Mou, Zhonglin

doi: 10.1104/pp.19.01242pmid: 31907298

Li, Qi; Wang, Chenggang; Mou, Zhonglin

doi: 10.1104/pp.19.01242pmid: 31907298

Multicellular eukaryotes including plants and animals have evolved highly complex, multilayered immune systems to fight off microbial infections. How the immune systems function is a fundamental question for immunologists. The animal immune system was originally thought to function by distinguishing between “self “and “nonself ”(the Self–Nonself model; Burnet, 1959), and later between “infectious-nonself” and “noninfectious-self” (the Infectious–Nonself model; Janeway, 1989, 1992). In 1994, Matzinger proposed that the immune system is more concerned with “danger” than with “non-self” (the Danger model; Matzinger, 1994, 2002, 2007). The Danger model suggests that the immune system is activated by danger/alarm signals that are sent from both microbial pathogens and damaged host cells. In this model, it is assumed that healthy cells or cells undergoing normal physiological death do not produce danger signals (Matzinger, 2002). Over the years, the Danger model has been supported by the discovery of a large number of endogenous danger signals (Tang et al., 2012; Pouwels et al., 2014; Schaefer, 2014; Hernandez et al., 2016; Yatim et al., 2017; Dinarello, 2018). Open in new tabDownload slide Open in new tabDownload slide Danger signals consist of conserved pathogen-associated molecular patterns (PAMPs) from the microbes and damage-associated molecular patterns (DAMPs) from injured host cells (Matzinger, 2002). Although the term “DAMPs” originally referred to the hydrophobic portions of biological molecules from dead and dying host and pathogen cells, which trigger immunity when exposed (Seong and Matzinger, 2004), it is now generally used to describe danger signals from damaged host cells (Martin, 2016; Yatim et al., 2017). Besides PAMPs and DAMPs, pathogen-derived effectors, which are proteins expressed by pathogens to aid infection of their hosts, and effector-caused perturbations on/in the host cells should also be considered as danger signals, though they were not included in the original model (Matzinger, 2002; Boller and Felix, 2009). PAMPs/DAMPs and extracellular effectors or their disturbances are generally recognized by germline-encoded cell-surface pattern recognition receptors (PRRs; Takeuchi and Akira, 2010), whereas intracellular effectors or their interruptions are often sensed by cytoplasmic nucleotide-binding oligomerization domain-like receptors (Chen et al., 2009). The plant immune system shares a similar conceptual logic with the animal immune system, though plants lack adaptive immunity (Nürnberger et al., 2004; Haney et al., 2014). A simple coevolutionary model called the “Zigzag” was proposed to describe the molecular events in plant–microbe interactions (Jones and Dangl, 2006). Based on this model, plant cells employ PRRs to detect PAMPs, activating PAMP-triggered immunity (PTI), while adapted pathogens utilize effectors to dampen PTI. Plants in turn exploit nucleotide-binding oligomerization domain-like receptors to sense the presence of effectors, leading to effector-triggered immunity, which usually culminates in a hypersensitive cell death response at the infection site. Natural selection constantly drives the arms race between plants and pathogens, resulting in different levels of pathogen virulence and plant resistance (Jones and Dangl, 2006). The Zigzag model has conceptually stimulated enormous research in the plant–microbe interaction field; however, it did not encompass DAMPs. The recent “Invasion” model included DAMPs and introduced a new term, “invasion patterns,” which essentially refers to the same type of molecules as “danger signals” (Cook et al., 2015). It was suggested that adapting the Danger model for plants would allow the holistic concept of host immunity to be better shared by the entire community of immunologists (Gust et al., 2017). Nevertheless, neither the Zigzag model nor the Invasion model accommodates systemic resistance, including systemic acquired resistance (SAR) and induced systemic resistance (ISR), which are also essential parts of the plant immune system (Durrant and Dong, 2004; Pieterse et al., 2014). SAR and ISR are two forms of induced resistance wherein the plant immune system is primed by a prior localized infection that results in resistance throughout the plant against subsequent challenge by a broad spectrum of pathogens. However, induction of the two forms of systemic resistance is mechanistically distinct. SAR depends on the immune signal molecule salicylic acid (SA), whereas ISR relies on the signaling pathways activated by the plant hormones jasmonic acid (JA) and ethylene (ET; Durrant and Dong, 2004; Pieterse et al., 2014). The SA, JA, and ET response pathways serve as the backbone of the plant immune signaling network (Pieterse et al., 2012). Compared to the large number of DAMPs that have been identified and characterized in animals, research on DAMPs in plants has only just begun (Rubartelli and Lotze, 2007; Choi and Klessig, 2016; Roh and Sohn, 2018). In the past several years, we have witnessed a marked increase in the number of potential DAMPs in plants, and the number is still growing (Table 1; Duran-Flores and Heil, 2016; Gust et al., 2017; Hou et al., 2019). Moreover, potential receptors for more than a dozen plant DAMPs have been identified (Gust et al., 2017; Hou et al., 2019). Characterization of these receptors is expected to significantly boost DAMP research in plants. While the DAMP field is blooming, the identity of DAMPs is under debate (Martin, 2016). It was argued in animals that a canonical DAMP should only be released from cells during necrosis; act through binding to cell-surface receptors; be upregulated, but not released, in response to PAMP detection or stress stimuli that are likely to presage necrosis; be synergistic with PAMPs in activating robust immune responses; and initiate relatively broad-acting responses in a manner similar to that shown by pathogen components (Martin, 2016). Based on these characteristics, members of the extended IL-1 cytokine family (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ) have been reasoned to be the canonical DAMPs activating the immune system, whereas most other proposed DAMPs, e.g. ATP, uric acid, calreticulin, HMGB1, HSPs, and DNA fragments, likely act through liberating IL-1 family cytokines via promoting necrosis (Martin, 2016). Putative DAMPs proposed in plants Table 1. Putative DAMPs proposed in plants Abbreviations: CAPE1, CYS-RICH SECRETORY PROTEINS, ANTIGEN5, AND PATHOGENESIS-RELATED1 PROTEINS (CAP)-DERIVED PEPTIDE1; eDNA, extracellular DNA; GmSubPep, G. max Subtilase Peptide; HMGB3, HIGH MOBILITY GROUP BOX3; HypSys, Hyp-rich Systemin; IDLp, INFLORESCENCE DEFICIENT IN ABSCISSION (IDA)-LIKE peptide; INR, INCEPTIN RECEPTOR; N/A, Not Applicable; RGS1, REGULATOR OF G-PROTEIN SIGNALING1; SCOOP12, SER-RICH ENDOGENOUS PEPTIDE12; Zip1, Z. mays immune signaling peptide1. DAMP . Precursor . N-Terminal Signal Peptide . Degree of Polymerization, Amino Acids, or Bps . Receptor . Plant . References . Primary/Constitutive DAMPs OGs Pectin N/A 10–15 WAK1 Arabidopsis Côté and Hahn, 1994; He et al., 1996; Brutus et al., 2010 eATP N/A N/A N/A DORN1 Arabidopsis Choi et al., 2014a; Roux, 2014 eNAD(P) N/A N/A N/A LecRK-I.8/VI.2 Arabidopsis Zhang and Mou, 2009; Wang et al., 2017a, 2019a Amino acids and glutathione N/A N/A N/A GLR3.3/3.6 Arabidopsis Qi et al., 2006; Stephens et al., 2008; Li et al., 2013; Toyota et al., 2018 Extracellular sugars N/A N/A N/A RGS1 Arabidopsis Johnston et al., 2007; Bolouri Moghaddam and van den Ende, 2012 HMGB3 N/A No N/A Unknown Arabidopsis Choi et al., 2016 Cutin monomers Cuticle N/A N/A Unknown Arabidopsis, tomato Fauth et al., 1998; Buxdorf et al., 2014 Cellooligomers Cellulose N/A 2–7 Unknown Arabidopsis Souza et al., 2017; Johnson et al., 2018 Xyloglucans Hemicellulose N/A 7–9 Unknown Common grape vine, Arabidopsis Claverie et al., 2018 Methanol Pectin N/A N/A Unknown Arabidopsis Dixit et al., 2013; Hann et al., 2014; Tran et al., 2018 eDNA fragments DNA N/A <700 Unknown Pea (Pisum sativum), lima bean (Phaseolus lunatus), maize, common bean Wen et al., 2009; Barbero et al., 2016; Duran-Flores and Heil, 2018 Secondary/Inducible DAMPs Systemin Prosystemin No 18 SYR1/2 Some Solanaceae species Pearce et al., 1991; Wang et al., 2018b HypSys ProHypSys Yes 18–20 Unknown Some Solanaceae species Pearce et al., 2001a; Pearce, 2011 Peps PROPEPs No 23 PEPR1/2 Arabidopsis, maize Huffaker et al., 2006, 2011, 2013; Yamaguchi et al., 2006, 2010 RALFs RALF preproproteins Yes 49 FER Tobacco, Arabidopsis Pearce et al., 2001b; Haruta et al., 2008, 2014; Stegmann et al., 2017 PSKs PSK precursors Yes 5 PSKR1/2 Asparagus, rice, Arabidopsis Matsubayashi and Sakagami, 1996; Yang et al., 1999, 2001; Matsubayashi et al., 2002; Amano et al., 2007 PIP1/2 PrePIP1/2 Yes 13/15 RLK7 Arabidopsis Hou et al., 2014 IDLp IDLs Yes 14 HAE/HSL2 Arabidopsis Stenvik et al., 2008; Butenko et al., 2014; Patharkar et al., 2017; Vie et al., 2017; Wang et al., 2017b GRIp GRI Yes 11 PRK5 Arabidopsis Wrzaczek et al., 2009, 2015 CAPE1 PR1 Yes 11 Unknown Tomato, Arabidopsis Chen et al., 2014 Zip1 PROZIP1 No 17 Unknown Maize Ziemann et al., 2018 Inceptins ATP synthase γ-subunit proteins No 11 INR Cowpea (Vigna unguiculata), maize Schmelz et al., 2006; Steinbrenner et al., 2019 GmSubPep Subtilase Yes 12 Unknown Soybean Pearce et al., 2010a GmPep914/890 GmPROPEP914/890 No 8 Unknown Soybean Yamaguchi et al., 2011 SCOOP12 PROSCOOP12 Yes 13 Unknown Arabidopsis Gully et al., 2019 DAMP . Precursor . N-Terminal Signal Peptide . Degree of Polymerization, Amino Acids, or Bps . Receptor . Plant . References . Primary/Constitutive DAMPs OGs Pectin N/A 10–15 WAK1 Arabidopsis Côté and Hahn, 1994; He et al., 1996; Brutus et al., 2010 eATP N/A N/A N/A DORN1 Arabidopsis Choi et al., 2014a; Roux, 2014 eNAD(P) N/A N/A N/A LecRK-I.8/VI.2 Arabidopsis Zhang and Mou, 2009; Wang et al., 2017a, 2019a Amino acids and glutathione N/A N/A N/A GLR3.3/3.6 Arabidopsis Qi et al., 2006; Stephens et al., 2008; Li et al., 2013; Toyota et al., 2018 Extracellular sugars N/A N/A N/A RGS1 Arabidopsis Johnston et al., 2007; Bolouri Moghaddam and van den Ende, 2012 HMGB3 N/A No N/A Unknown Arabidopsis Choi et al., 2016 Cutin monomers Cuticle N/A N/A Unknown Arabidopsis, tomato Fauth et al., 1998; Buxdorf et al., 2014 Cellooligomers Cellulose N/A 2–7 Unknown Arabidopsis Souza et al., 2017; Johnson et al., 2018 Xyloglucans Hemicellulose N/A 7–9 Unknown Common grape vine, Arabidopsis Claverie et al., 2018 Methanol Pectin N/A N/A Unknown Arabidopsis Dixit et al., 2013; Hann et al., 2014; Tran et al., 2018 eDNA fragments DNA N/A <700 Unknown Pea (Pisum sativum), lima bean (Phaseolus lunatus), maize, common bean Wen et al., 2009; Barbero et al., 2016; Duran-Flores and Heil, 2018 Secondary/Inducible DAMPs Systemin Prosystemin No 18 SYR1/2 Some Solanaceae species Pearce et al., 1991; Wang et al., 2018b HypSys ProHypSys Yes 18–20 Unknown Some Solanaceae species Pearce et al., 2001a; Pearce, 2011 Peps PROPEPs No 23 PEPR1/2 Arabidopsis, maize Huffaker et al., 2006, 2011, 2013; Yamaguchi et al., 2006, 2010 RALFs RALF preproproteins Yes 49 FER Tobacco, Arabidopsis Pearce et al., 2001b; Haruta et al., 2008, 2014; Stegmann et al., 2017 PSKs PSK precursors Yes 5 PSKR1/2 Asparagus, rice, Arabidopsis Matsubayashi and Sakagami, 1996; Yang et al., 1999, 2001; Matsubayashi et al., 2002; Amano et al., 2007 PIP1/2 PrePIP1/2 Yes 13/15 RLK7 Arabidopsis Hou et al., 2014 IDLp IDLs Yes 14 HAE/HSL2 Arabidopsis Stenvik et al., 2008; Butenko et al., 2014; Patharkar et al., 2017; Vie et al., 2017; Wang et al., 2017b GRIp GRI Yes 11 PRK5 Arabidopsis Wrzaczek et al., 2009, 2015 CAPE1 PR1 Yes 11 Unknown Tomato, Arabidopsis Chen et al., 2014 Zip1 PROZIP1 No 17 Unknown Maize Ziemann et al., 2018 Inceptins ATP synthase γ-subunit proteins No 11 INR Cowpea (Vigna unguiculata), maize Schmelz et al., 2006; Steinbrenner et al., 2019 GmSubPep Subtilase Yes 12 Unknown Soybean Pearce et al., 2010a GmPep914/890 GmPROPEP914/890 No 8 Unknown Soybean Yamaguchi et al., 2011 SCOOP12 PROSCOOP12 Yes 13 Unknown Arabidopsis Gully et al., 2019 Open in new tab Table 1. Putative DAMPs proposed in plants Abbreviations: CAPE1, CYS-RICH SECRETORY PROTEINS, ANTIGEN5, AND PATHOGENESIS-RELATED1 PROTEINS (CAP)-DERIVED PEPTIDE1; eDNA, extracellular DNA; GmSubPep, G. max Subtilase Peptide; HMGB3, HIGH MOBILITY GROUP BOX3; HypSys, Hyp-rich Systemin; IDLp, INFLORESCENCE DEFICIENT IN ABSCISSION (IDA)-LIKE peptide; INR, INCEPTIN RECEPTOR; N/A, Not Applicable; RGS1, REGULATOR OF G-PROTEIN SIGNALING1; SCOOP12, SER-RICH ENDOGENOUS PEPTIDE12; Zip1, Z. mays immune signaling peptide1. DAMP . Precursor . N-Terminal Signal Peptide . Degree of Polymerization, Amino Acids, or Bps . Receptor . Plant . References . Primary/Constitutive DAMPs OGs Pectin N/A 10–15 WAK1 Arabidopsis Côté and Hahn, 1994; He et al., 1996; Brutus et al., 2010 eATP N/A N/A N/A DORN1 Arabidopsis Choi et al., 2014a; Roux, 2014 eNAD(P) N/A N/A N/A LecRK-I.8/VI.2 Arabidopsis Zhang and Mou, 2009; Wang et al., 2017a, 2019a Amino acids and glutathione N/A N/A N/A GLR3.3/3.6 Arabidopsis Qi et al., 2006; Stephens et al., 2008; Li et al., 2013; Toyota et al., 2018 Extracellular sugars N/A N/A N/A RGS1 Arabidopsis Johnston et al., 2007; Bolouri Moghaddam and van den Ende, 2012 HMGB3 N/A No N/A Unknown Arabidopsis Choi et al., 2016 Cutin monomers Cuticle N/A N/A Unknown Arabidopsis, tomato Fauth et al., 1998; Buxdorf et al., 2014 Cellooligomers Cellulose N/A 2–7 Unknown Arabidopsis Souza et al., 2017; Johnson et al., 2018 Xyloglucans Hemicellulose N/A 7–9 Unknown Common grape vine, Arabidopsis Claverie et al., 2018 Methanol Pectin N/A N/A Unknown Arabidopsis Dixit et al., 2013; Hann et al., 2014; Tran et al., 2018 eDNA fragments DNA N/A <700 Unknown Pea (Pisum sativum), lima bean (Phaseolus lunatus), maize, common bean Wen et al., 2009; Barbero et al., 2016; Duran-Flores and Heil, 2018 Secondary/Inducible DAMPs Systemin Prosystemin No 18 SYR1/2 Some Solanaceae species Pearce et al., 1991; Wang et al., 2018b HypSys ProHypSys Yes 18–20 Unknown Some Solanaceae species Pearce et al., 2001a; Pearce, 2011 Peps PROPEPs No 23 PEPR1/2 Arabidopsis, maize Huffaker et al., 2006, 2011, 2013; Yamaguchi et al., 2006, 2010 RALFs RALF preproproteins Yes 49 FER Tobacco, Arabidopsis Pearce et al., 2001b; Haruta et al., 2008, 2014; Stegmann et al., 2017 PSKs PSK precursors Yes 5 PSKR1/2 Asparagus, rice, Arabidopsis Matsubayashi and Sakagami, 1996; Yang et al., 1999, 2001; Matsubayashi et al., 2002; Amano et al., 2007 PIP1/2 PrePIP1/2 Yes 13/15 RLK7 Arabidopsis Hou et al., 2014 IDLp IDLs Yes 14 HAE/HSL2 Arabidopsis Stenvik et al., 2008; Butenko et al., 2014; Patharkar et al., 2017; Vie et al., 2017; Wang et al., 2017b GRIp GRI Yes 11 PRK5 Arabidopsis Wrzaczek et al., 2009, 2015 CAPE1 PR1 Yes 11 Unknown Tomato, Arabidopsis Chen et al., 2014 Zip1 PROZIP1 No 17 Unknown Maize Ziemann et al., 2018 Inceptins ATP synthase γ-subunit proteins No 11 INR Cowpea (Vigna unguiculata), maize Schmelz et al., 2006; Steinbrenner et al., 2019 GmSubPep Subtilase Yes 12 Unknown Soybean Pearce et al., 2010a GmPep914/890 GmPROPEP914/890 No 8 Unknown Soybean Yamaguchi et al., 2011 SCOOP12 PROSCOOP12 Yes 13 Unknown Arabidopsis Gully et al., 2019 DAMP . Precursor . N-Terminal Signal Peptide . Degree of Polymerization, Amino Acids, or Bps . Receptor . Plant . References . Primary/Constitutive DAMPs OGs Pectin N/A 10–15 WAK1 Arabidopsis Côté and Hahn, 1994; He et al., 1996; Brutus et al., 2010 eATP N/A N/A N/A DORN1 Arabidopsis Choi et al., 2014a; Roux, 2014 eNAD(P) N/A N/A N/A LecRK-I.8/VI.2 Arabidopsis Zhang and Mou, 2009; Wang et al., 2017a, 2019a Amino acids and glutathione N/A N/A N/A GLR3.3/3.6 Arabidopsis Qi et al., 2006; Stephens et al., 2008; Li et al., 2013; Toyota et al., 2018 Extracellular sugars N/A N/A N/A RGS1 Arabidopsis Johnston et al., 2007; Bolouri Moghaddam and van den Ende, 2012 HMGB3 N/A No N/A Unknown Arabidopsis Choi et al., 2016 Cutin monomers Cuticle N/A N/A Unknown Arabidopsis, tomato Fauth et al., 1998; Buxdorf et al., 2014 Cellooligomers Cellulose N/A 2–7 Unknown Arabidopsis Souza et al., 2017; Johnson et al., 2018 Xyloglucans Hemicellulose N/A 7–9 Unknown Common grape vine, Arabidopsis Claverie et al., 2018 Methanol Pectin N/A N/A Unknown Arabidopsis Dixit et al., 2013; Hann et al., 2014; Tran et al., 2018 eDNA fragments DNA N/A <700 Unknown Pea (Pisum sativum), lima bean (Phaseolus lunatus), maize, common bean Wen et al., 2009; Barbero et al., 2016; Duran-Flores and Heil, 2018 Secondary/Inducible DAMPs Systemin Prosystemin No 18 SYR1/2 Some Solanaceae species Pearce et al., 1991; Wang et al., 2018b HypSys ProHypSys Yes 18–20 Unknown Some Solanaceae species Pearce et al., 2001a; Pearce, 2011 Peps PROPEPs No 23 PEPR1/2 Arabidopsis, maize Huffaker et al., 2006, 2011, 2013; Yamaguchi et al., 2006, 2010 RALFs RALF preproproteins Yes 49 FER Tobacco, Arabidopsis Pearce et al., 2001b; Haruta et al., 2008, 2014; Stegmann et al., 2017 PSKs PSK precursors Yes 5 PSKR1/2 Asparagus, rice, Arabidopsis Matsubayashi and Sakagami, 1996; Yang et al., 1999, 2001; Matsubayashi et al., 2002; Amano et al., 2007 PIP1/2 PrePIP1/2 Yes 13/15 RLK7 Arabidopsis Hou et al., 2014 IDLp IDLs Yes 14 HAE/HSL2 Arabidopsis Stenvik et al., 2008; Butenko et al., 2014; Patharkar et al., 2017; Vie et al., 2017; Wang et al., 2017b GRIp GRI Yes 11 PRK5 Arabidopsis Wrzaczek et al., 2009, 2015 CAPE1 PR1 Yes 11 Unknown Tomato, Arabidopsis Chen et al., 2014 Zip1 PROZIP1 No 17 Unknown Maize Ziemann et al., 2018 Inceptins ATP synthase γ-subunit proteins No 11 INR Cowpea (Vigna unguiculata), maize Schmelz et al., 2006; Steinbrenner et al., 2019 GmSubPep Subtilase Yes 12 Unknown Soybean Pearce et al., 2010a GmPep914/890 GmPROPEP914/890 No 8 Unknown Soybean Yamaguchi et al., 2011 SCOOP12 PROSCOOP12 Yes 13 Unknown Arabidopsis Gully et al., 2019 Open in new tab In plants, the identity of DAMPs has not been vigorously debated. Recently, immunogenic plant factors were roughly divided into two categories, primary and secondary DAMPs, which correspond to constitutive and inducible DAMPs proposed in animals (Gust et al., 2017; Yatim et al., 2017). Primary/constitutive DAMPs are derived from pre-existing structures or molecules, including breakdown products of extracellular matrix and passively released intracellular molecules, while secondary/inducible DAMPs are actively processed and released upon tissue damage and other stimuli (Gust et al., 2017). Although this delineation of primary DAMPs is aligned with the original definition of DAMPs (Matzinger, 2002; Seong and Matzinger, 2004), it is worthwhile to compare the secondary DAMPs with the proposed canonical DAMPs in animals (Martin, 2016). One central argument for members of the extended IL-1 family being the canonical DAMPs in animals is that they do not possess N-terminal signal sequences and are released during necrosis (Martin, 2016). In contrast, precursors of most of the candidate peptide DAMPs in plants carry an N-terminal signal peptide (Table 1), suggesting active release via the conventional secretion pathway. They would, nevertheless, also be passively released upon cell damage during microbial infection and herbivore attack. Thus, besides being DAMPs under pathological conditions, such molecules may function in normal physiological processes. In this review, we focus on several proposed plant primary and secondary DAMPs and their receptors, which have been shown to physically bind each other. For a complete inventory of potential DAMPs in plants, we refer interested readers to several recent excellent reviews and references therein (Choi and Klessig, 2016; Duran-Flores and Heil, 2016; Gust et al., 2017; Hou et al., 2019). A new item that was recently added to the inventory is the Arabidopsis (Arabidopsis thaliana) SCOOP12 peptide, which is perceived by plants in a BRASSINOSTEROID INSENSITIVE1 (BRI1)-ASSOCIATED KINASE1 (BAK1) coreceptor-dependent manner (Table 1; Gully et al., 2019). We explore potential roles of DAMPs in plant immunity, particularly in SAR. Future perspectives of DAMPs in plants are also discussed. PRIMARY/CONSTITUTIVE DAMP-RECEPTOR PAIRS Oligogalacturonides—WALL-ASSOCIATED KINASE1 Oligogalacturonides (OGs) are degradation products of the primary cell wall component pectin, a complex polysaccharide comprising mainly esterified d-GalUA residues in α-(1-4)-chain (Côté and Hahn, 1994; Ferrari et al., 2013; Kohorn, 2016). Pectin is partially degraded by pathogen- or plant-derived enzymes during pathogen infection or herbivore attack, resulting in oligomers of d-galacturonic acids with varying degrees of polymerization (Bishop et al., 1981; Côté and Hahn, 1994; Bergey et al., 1999; An et al., 2005). OGs with a degree of polymerization between 10 and 15 are potent elicitors (Côté and Hahn, 1994; Moscatiello et al., 2006; Ferrari et al., 2007; Denoux et al., 2008), able to induce reactive oxygen species (ROS) production, MAP kinase activation, callose deposition, defense protein accumulation, and resistance to the necrotrophic fungal pathogen Botrytis cinerea in multiple plant species (Hahn et al., 1981; Davis and Hahlbrock, 1987; Broekaert and Peumans, 1988; Bellincampi et al., 2000; Aziz et al., 2004; Denoux et al., 2008; Galletti et al., 2008; Rasul et al., 2012). Short OGs with a degree of polymerization between two and six have also been shown to elicit immune responses, but the effect of short OGs on the expression of immune-related genes appears to be not as strong as that of long OGs (Moloshok et al., 1992; Davidsson et al., 2017). WALL-ASSOCIATED KINASE (WAK) proteins are proposed receptors of OGs (Kohorn and Kohorn, 2012; Ferrari et al., 2013). WAKs are receptor-like kinases (RLKs), with an extracellular domain containing epidermal growth factor motifs, a transmembrane domain, and an intracellular Ser/Thr kinase domain (He et al., 1996; Anderson et al., 2001). There are five WAK and 21 WAK-LIKE genes in Arabidopsis (Anderson et al., 2001; Verica and He, 2002). Biochemical analyses suggested that WAK1 is tightly associated with pectin (He et al., 1996; Wagner and Kohorn, 2001). The extracellular domains of WAK1 and WAK2 indeed bind pectin in vitro (Kohorn et al., 2009). A recombinant peptide containing amino acids 67 to 254 of the extracellular domain of WAK1 (called “WAK67–254”) binds polygalacturonic acid (PGA), OGs, pectins, and structurally related alginates (Decreux and Messiaen, 2005). At least five specific amino acids in the extracellular domain of WAK1 are involved in the interaction with PGA (Decreux et al., 2006). Interestingly, binding of WAK67–254 to PGA, OGs, and alginates depends on Ca2+ and ionic conditions that promote formation of Ca2+ bridges between oligomers or polymers, resulting in a structure known as an “egg-box dimer,” which significantly enhances binding to WAK1 and induces increased extracellular alkalinization when applied to Arabidopsis cell suspensions (Decreux and Messiaen, 2005; Cabrera et al., 2008). Multiple lines of genetic evidence strongly support that WAKs are OG receptors and function in plant immune responses. First, a chimeric receptor with the extracellular domain of WAK1 and the kinase domain of ELONGATION FACTOR Tu receptor (EFR) responds to OGs and activates the kinase domain, and conversely, elf18, a polypeptide consisting of the first 18 amino acids at the N terminus of ELONGATION FACTOR Tu, activates a chimeric receptor formed by the EFR ectodomain and the kinase domain of WAK1 and induces the typical responses triggered by OGs (Brutus et al., 2010). Second, pectin- and OG-induced transcription of a number of genes depends on WAK2 in Arabidopsis protoplasts (Kohorn et al., 2009, 2012). Third, pathogen infection and SA treatment induce WAK1 gene expression and the induction depends on NONEXPRESSOR OF PATHOGENESIS-RELATED (PR) GENES1 (NPR1), a key immune regulator (Cao et al., 1997; He et al., 1998). SA also induces the expression of WAK2, WAK3, and WAK5 (He et al., 1999), and WAK1 and WAK2 are wound-inducible as well (Wagner and Kohorn, 2001). Fourth, overexpression of WAK1 enhances tolerance to SA toxicity, and expression of an antisense allele of WAK1 reduces the level of PR1 gene expression induced by the biologically active analog of SA, 2.6-dichloroisonicotinic acid (He et al., 1998). Fifth, a dominant gain-of-function WAK2 allele, WAK2cTAP, exhibits autoimmune phenotypes including ROS accumulation and cell death (Kohorn et al., 2009, 2012). Importantly, the stunted growth phenotype of WAK2cTAP is largely suppressed by mutations in the key immune regulators, ENHANCED DISEASE SUSCEPTIBILITY1, PHYTOALEXIN DEFICIENT4, and MAP KINASE6 (MPK6) genes (Kohorn et al., 2012, 2014), which is reminiscent of autoimmune phenotypes (van Wersch et al., 2016). Extracellular ATP-DOES NOT RESPOND TO NUCLEOTIDES1 Extracellular ATP (eATP) is one of the best-studied DAMPs in animals. As the energy currency, cellular levels of ATP are normally maintained in the range of 1 to 10 mm. In animals, ATP is constitutively released into the extracellular space through various mechanisms including ATP binding cassette transporters, vesicular exocytosis, gap junctions, and pannexin hemichannels, as well as the P2X7 receptor (Lazarowski et al., 2003; Spray et al., 2006; Suadicani et al., 2006; Zhang et al., 2007). ATP also leaks into the extracellular milieu upon cell lysis or necrosis during tissue damage and inflammation (la Sala et al., 2003). Once in the extracellular milieu, ATP binds to either P2X ligand-gated channels or P2Y G-protein coupled receptors, triggering outside–in signaling including changes in intracellular [Ca2+], production of cytokines, and cell death (Hattori and Gouaux, 2012; Jacobson et al., 2015). Depending on the tissue and cell types, eATP signaling acts in both normal physiological and abnormal pathological processes in animals (Trautmann, 2009). In plants, research with exogenous ATP can be traced back to the 1960s (Jaffe and Galston, 1966). However, it was unclear in the early studies whether the exogenously added ATP functioned as a signal molecule, a precursor, or an energy supply (Jaffe and Galston, 1966; Williamson, 1975; Kamizyo and Tanaka, 1982; Nejidat et al., 1983). Recent studies with the widely used stable ATP analog, adenosine 5′-[γ-thio]triphosphate, suggested that eATP might act as a signal molecule in the apoplast (Jeter et al., 2004; Song et al., 2006; Torres et al., 2008; Clark et al., 2010, 2011). The presence of eATP was proven by directly measuring ATP accumulation in Arabidopsis leaves and roots (Thomas et al., 1999; Demidchik et al., 2003; Deng et al., 2015), and active secretion of ATP in plants was confirmed by feeding Arabidopsis cultures with [32P]H3PO4 and monitoring radiolabeled ATP in the extracellular matrix (Chivasa et al., 2005). Furthermore, the distribution of eATP in plants was directly visualized using luciferase reporters including a cellulose-binding domain-luciferase fusion, an ecto-luciferase, and the infiltration of a luciferase/luciferin mixture (Kim et al., 2006; Chivasa et al., 2009; Clark et al., 2011). These tools allowed discoveries of the dynamics of eATP accumulation in roots, leaves, and around guard cells (Kim et al., 2006; Chivasa et al., 2009; Clark et al., 2011). The constitutive eATP appears to be essential for plant cell viability. Depletion of basal eATP using the cell-impermeant traps Glc-hexokinase and apyrase triggers cell death in both Arabidopsis cell cultures and whole plants (Chivasa et al., 2005). Competitive exclusion of eATP from its binding sites with nonhydrolyzable ATP analog β,γ-methyleneadenosine 5′-triphosphate also results in cell death in Arabidopsis, maize (Zea mays), bean (Phaseolus vulgaris), and tobacco (Nicotiana tabacum; Chivasa et al., 2005). Interestingly, the programmed cell death-eliciting mycotoxin fumonisin B1-induced cell death in Arabidopsis seems to be mediated by depletion of eATP (Chivasa et al., 2005). Furthermore, environmental stresses induce ATP release (Clark et al., 2011; Sun et al., 2012; Lim et al., 2014; Deng et al., 2015). Although the biological relevance of the increases in endogenous eATP levels remains to be fully elucidated, studies with exogenous ATP and/or adenosine 5′-[γ-thio]triphosphate have shown that eATP induces ROS and nitric oxide production, Ca2+ influx, and H+ efflux in a G protein α-subunit and RESPIRATORY BURST OXIDASE HOMOLOG (RBOH)-dependent manner (Jeter et al., 2004; Song et al., 2006; Foresi et al., 2007; Wu et al., 2008; Wu and Wu, 2008; Demidchik et al., 2009; Clark et al., 2011; Hao et al., 2012; Sun et al., 2012). Intriguingly, plants appear to respond to eATP in a dose-dependent manner. Low doses of eATP induce stomatal opening, accelerate vesicular trafficking, and stimulate cell elongation, whereas high doses of eATP trigger stomatal closure, inhibit vesicular trafficking, and suppress cell elongation (Clark et al., 2010, 2011, 2013; Wang et al., 2014; Deng et al., 2015). Although depletion of eATP or exclusion of eATP from its binding sites leads to cell death, high doses of eATP also reduce cell viability (Sun et al., 2012; Deng et al., 2015). Currently, the molecular mechanisms underlying such biphasic responses are unknown. Identification of the eATP receptor DOES NOT RESPOND TO NUCLEOTIDES1 (DORN1) in Arabidopsis is a major breakthrough in eATP biology and provided a key to addressing many questions about eATP (Choi et al., 2014a; Roux, 2014). DORN1 is a legume-type lectin receptor kinase (LecRK), LecRK-I.9, which had previously been shown to recognize RGD (Arg-Gly-Asp) tripeptide motif-containing protein in mediating plasma membrane-cell wall adhesions (Gouget et al., 2006). The extracellular domain of DORN1 binds ATP with a dissociation constant (Kd) of ∼46 nm (Choi et al., 2014a). A point mutation in the DORN1 gene completely blocks exogenous ATP-induced transcriptional changes in Arabidopsis seedlings, indicating that DORN1 is the major, if not the sole, receptor of eATP (Choi et al., 2014a). However, as eATP plays an important role in plant growth, development, and cell viability (Tang et al., 2003; Chivasa et al., 2005; Clark and Roux, 2011; Liu et al., 2012; Yang et al., 2015), but dorn1 mutants do not have obvious growth and developmental defects (Choi et al., 2014a), it has been suggested that there might be other eATP receptors mainly regulating plant growth signaling (Roux, 2014). It was recently proposed that eATP functions as a DAMP in plants (Choi et al., 2014b; Tanaka et al., 2014). Indeed, eATP levels at the wound sites reach ∼40 μm, well above the concentration needed to induce ROS production and gene expression (Choi et al., 2014a), and reducing eATP levels by overexpressing an apyrase suppresses wound responses (Song et al., 2006; Wang et al., 2019b). Furthermore, ∼60% of the genes induced by exogenous ATP are also induced by wounding (Choi et al., 2014a), and ATP mainly activates JA signaling through MYC transcription factors (Tripathi et al., 2018; Jewell et al., 2019). Therefore, eATP clearly plays an important role in wound responses. Furthermore, exogenous ATP induces resistance to the necrotrophic fungal pathogen B. cinerea in Arabidopsis (Tripathi et al., 2018), suggesting a potential role for eATP in immunity against fungal pathogens. Interestingly, although more than a dozen ATP-induced genes depend on NPR1 (Jewell et al., 2019), eATP and SA antagonize each other (Chivasa et al., 2009). Exogenous ATP reduces basal SA levels, whereas SA treatment triggers collapse of eATP in tobacco leaves (Chivasa et al., 2009). In line with these results, exogenous ATP does not induce apoplastic resistance to Pseudomonas syringae pv. maculicola strain ES4326 in Arabidopsis (Zhang and Mou, 2009). On the other hand, eATP plays an important positive role in stomatal immunity. In Arabidopsis, bacterial infection induces ATP release, particularly around guard cells, and exogenous ATP induces stomatal closure and stomatal resistance against bacterial pathogens in a concentration-dependent manner (Chen et al., 2017). Importantly, exogenous ATP-induced stomatal movement and resistance depend on DORN1 and RBOHD. It was proposed that eATP activates DORN1, which in turn phosphorylates the N terminus of RBOHD, leading to ROS production that induces stomatal closure (Chen et al., 2017). Extracellular NAD(P)—LecRK-I.8/LecRK-VI.2 It is well known that extracellular NAD (eNAD) and NADP (eNADP) play a significant role in animal immune responses (Billington et al., 2006; Haag et al., 2007; Adriouch et al., 2012). However, whether eNAD(P) is a DAMP in animals remains elusive (Roh and Sohn, 2018). Under normal conditions, intracellular NAD+ levels are in the range of 0.2 to 0.5 mm (Cantó et al., 2015), whereas eNAD levels, e.g. in mammalian serum, are ∼0.1 μm (Zocchi et al., 1999; O’Reilly and Niven, 2003). Cell lysis during tissue damage and inflammation presumably can lead to dramatic increases in eNAD(P) levels (Billington et al., 2006). At least three distinct mechanisms perceive eNAD(P) in animals. First, eNAD(P) can be processed by a number of NAD(P)-metabolizing ectoenzymes such as CD38 and CD157, which have ADP-ribosyl cyclase, cADP-ribose hydrolase and NAD-hydrolase activities, into Ca2+-mobilizing second messengers cADP-ribose and nicotinic acid adenine dinucleotide phosphate (Ceni et al., 2003; Partida-Sánchez et al., 2003; de Flora et al., 2004; Heidemann et al., 2005; Malavasi et al., 2006). Second, eNAD+ is a substrate of the GPI-anchored or secreted ectoenzymes known as mono(ADP-ribosyl)transferases in ADP-ribosylation of plasma membrane signaling proteins (Nemoto et al., 1996; Han et al., 2000; Bannas et al., 2005). Finally, eNAD(P) is a potential agonist of plasma membrane receptors. It has previously been shown that NAD+ binds to rat brain synaptic membranes and is a potential inhibitory neurotransmitter (Khalmuradov et al., 1983; Mutafova-Yambolieva et al., 2007). Recent studies have suggested that several purinergic P2X and P2Y receptors function in eNAD(P)-triggered biological responses (Moreschi et al., 2006; Mutafova-Yambolieva et al., 2007; Grahnert et al., 2009; Klein et al., 2009). Nevertheless, binding between NAD(P) and these receptors has not been reported. In plants, intracellular NAD(P) levels are in the range of 1 to 2 mm (Noctor et al., 2006). We found that, upon wounding and bacterial infection, NAD(P) concentrations in the extracellular washing fluid are comparable to those from infiltration with ∼0.7 and ∼1.2 mm of NAD(P), respectively (Zhang and Mou, 2009). We also showed that treatment of Arabidopsis and citrus plants with 0.2 mm of NAD(P) significantly induces resistance to bacterial pathogens, but not to the necrotrophic fungal pathogen B. cinerea (Zhang and Mou, 2009; Wang et al., 2016; Alferez et al., 2018). Importantly, exogenously applied NAD(P) does not change intracellular NAD(P) homeostasis (Zhang and Mou, 2009), suggesting that it acts in the apoplast. Furthermore, we found that transgenic expression of the human CD38 gene in Arabidopsis reduces eNAD(P) concentrations and partially compromises SAR (Zhang and Mou, 2012). These results together indicate that the eNAD(P) accumulated during pathogen infection is both necessary and sufficient for activation of plant immune responses. In addition, exogenous NAD(P) induces ROS production and changes in cytosolic [Ca2+] (Pétriacq et al., 2016a, 2016b). Thus, eNAD(P) is a DAMP in plants. Using a reverse genetic approach based on exogenous NAD+-induced transcriptome changes in Arabidopsis, we have identified two potential eNAD(P) receptors, LecRK-I.8 and LecRK-VI.2, both of which are legume-type LecRKs (Singh et al., 2012; Wang et al., 2017a, 2019a). The LecRK-I.8 and LecRK-VI.2 genes can be induced by exogenous NAD+, and both LecRK-I.8 and LecRK-VI.2 are localized in the plasma membrane and have kinase activity (Xin et al., 2009; Singh et al., 2013; Wang et al., 2017a). However, the two receptors are not alike. LecRK-I.8 only binds NAD+ (Kd, ∼437 nm), whereas LecRK-VI.2 binds both NAD+ and NADP+ with a slightly higher affinity for NADP+ (Wang et al., 2017a, 2019a). LecRK-VI.2 binds 32P-NAD+ with a Kd of ∼787 nm, and the binding can be effectively competed by unlabeled NAD+ (50% inhibition concentration, IC50, 1,887 nm) and NADP+ (IC50, 945 nm; Wang et al., 2019a). Consistently, mutations in LecRK-I.8 and LecRK-VI.2 suppress NAD+- and NADP+-induced immune responses, respectively (Wang et al., 2017a, 2019a). Interestingly, the lecrk-I.8/VI.2 double mutant behaves like lecrk-I.8 for NAD+ responses and like lecrk-VI.2 for NADP+ responses, indicating that the two receptors function in two separate pathways (Wang et al., 2019a). Importantly, mutations in LecRK-I.8 and LecRK-VI.2 significantly compromise basal immunity and biological induction of SAR, respectively (Wang et al., 2017a, 2019a), indicating that LecRK-I.8 primarily functions in basal immunity, whereas LecRK-VI.2 plays a major role in SAR. The Leu-rich repeat receptor kinase (LRR-RK) BAK1 is a coreceptor of a group of LRR-RK receptors including BRI1, FLAGELLIN-SENSITIVE2 (FLS2), EFR, and PEP RECEPTOR1 (PEPR1)/PEPR2 (Li et al., 2002a; Nam and Li, 2002; Chinchilla et al., 2007; Heese et al., 2007; Postel et al., 2010; Schulze et al., 2010; Roux et al., 2011). BAK1 is also required for signaling triggered by several other potential DAMPs including the Arabidopsis HMGB3 protein and the SCOOP12 peptide (Choi et al., 2016; Gully et al., 2019). BAK1 and LecRK-VI.2 form a complex in vivo and function in eNAD(P) signaling and SAR (Wang et al., 2019a). The interaction between BAK1 and LecRK-VI.2 appears to be constitutive and independent of eNAD(P), which is different from the inducible associations between BAK1 and LRR-RK receptors. Moreover, the bak1-5 mutation has been shown to impair signaling mediated by the non-RD kinases FLS and EFR, but not that mediated by the RD kinase BRI1 (Schwessinger et al., 2011). Interestingly, although LecRK-VI.2 is an RD kinase, eNAD(P) signaling is significantly inhibited in bak1-5 (Wang et al., 2019a). In addition, it has been shown that C-terminal tags on BAK1 have limited effects on several BR responses, but strongly impact PTI signaling (Ntoukakis et al., 2011). Surprisingly, a BAK1-GFP fusion protein is able to complement the defects of bak1-5 in NADP+-induced immune responses and biological induction of SAR (Wang et al., 2019a). Because C-terminally tagged BAK1 fusion proteins are not phosphorylated at S612 upon PAMP treatment (Perraki et al., 2018), it would be interesting to test whether S612 phosphorylation in BAK1 is required for eNAD(P) signaling and SAR. Interestingly, exogenously added NAD+ moves systemically and induces systemic resistance (Wang et al., 2019a), suggesting that eNAD(P) might be an SAR mobile signal. Consistently, high levels of exogenous NAD(P) induces SA accumulation and NADPH oxidase-independent ROS production (Zhang and Mou, 2009; Pétriacq et al., 2016b). Surprisingly, exogenous NAD(P)-induced systemic immunity does not depend on the putative SAR mobile signals pipecolic acid (Pip), N-hydroxy-Pip, azelaic acid (AzA), and glycerol-3-phosphate (G3P), but requires an intact SA signaling pathway (Wang et al., 2019a). Although the role of DEFECTIVE IN INDUCED RESISTANCE1 (DIR1) and ROS in NAD(P)-induced systemic immunity has not been tested, exogenous NAD(P)-induced local resistance and PR gene expression is independent of DIR1 and NADPH oxidase, respectively (Zhang and Mou, 2009; Wang et al., 2019a). It appears that eNAD(P) functions either downstream or independently of the putative SAR mobile signals Pip, N-hydroxy-Pip, AzA, G3P, DIR1, and ROS in both local and systemic resistance. Furthermore, although exogenous eNAD(P) requires SA signaling for immune response activation, SA induces the expression of LecRK-VI.2 in an NPR1-dependent manner (Wang et al., 2019a). In addition, because Pip, ROS, AzA, and G3P form a signaling amplification loop (Wang et al., 2018a), it is possible that ROS produced in the amplification loop causes reversible or irreversible damages to the plasma membrane (Cwiklik and Jungwirth, 2010; Tero et al., 2016), leading to leakage of cellular NAD(P) into the apoplast. Thus, the interplay between eNAD(P) and SA as well as other SAR signal molecules is complicated and deserves further investigation. Glu—GLU-RECEPTOR3.3/GLU-RECEPTOR3.6 Glu is the most prominent neurotransmitter in the brain and excites postsynaptic neural cells through different types of receptors including ionotropic and metabotropic Glu receptors (Brassai et al., 2015). Ionotropic Glu receptors (iGluRs) are ligand-gated channels that are activated upon Glu binding (Krieger et al., 2019). The Arabidopsis genome encodes 20 GLU-RECEPTORs (GLRs) that are homologous to iGluRs (Chiu et al., 2002). GLRs carry the same signature domains as animal iGluRs, including the “three-plus-one” transmembrane domains and the extracellular ligand-binding domains (Lam et al., 1998; Chiu et al., 1999; Lacombe et al., 2001). Upon herbivore and mechanical damage, Glu is released into the apoplast where it activates GLR3.3 and GLR3.6, triggering long-distance electric and Ca2+ signaling as well as JA accumulation and defense gene expression in undamaged leaves (Mousavi et al., 2013; Toyota et al., 2018). At least six amino acids (Glu, Gly, Ala, Ser, Asn, and Cys) and the tripeptide glutathione can also serve as agonists of GLR3.3 and induce membrane depolarization and cytosolic [Ca2+] elevation in a GLR3.3-dependent manner (Qi et al., 2006; Stephens et al., 2008; Li et al., 2013). Moreover, seven out of the 20 standard amino acids (Met, Trp, Phe, Leu, Tyr, Asn, and Thr) activate GLR1.4 transiently expressed in Xenopus oocytes to various extents, and Met-induced membrane depolarization in Arabidopsis leaves depends on GLR1.4 (Tapken et al., 2013). Interestingly, several amino acids have been shown to induce disease resistance in plants. For instance, His induces ET biosynthesis and ET-related defense gene expression as well as resistance to the soil-borne bacterial pathogen Ralstonia solanacearum and the fungal pathogen B. cinerea partially in an ET-dependent manner in tomato (Solanum lycopersicum) and Arabidopsis (Seo et al., 2016). Glu induces several genes of the SA signaling pathway in rice (Oryza sativa) and tomato fruit, and enhances resistance to Magnaporthe oryzae and Alternaria alternata in rice and tomato fruit, respectively (Kadotani et al., 2016; Yang et al., 2017). Surprisingly, other amino acids except Trp and Tyr also improve rice resistance to M. oryzae to various degrees (Kadotani et al., 2016). Furthermore, Cys, Asp, and GSH enhance resistance to P seudomonas syringae pv. tomato (Pst) DC3000 in Arabidopsis (Li et al., 2013). Importantly, Cys- and GSH-induced disease resistance depends on GLR3.3, and mutations of the GLR3.3 gene compromise resistance to Pst DC3000 and Hyaloperonospora arabidopsidis in Arabidopsis (Li et al., 2013; Manzoor et al., 2013), suggesting that GLR3.3 is a potential receptor for Cys and GSH released into the apoplast during pathogen infection. SECONDARY/ INDUCIBLE DAMP-RECEPTOR PAIRS Systemin—Systemin Receptor1/Systemin Receptor2 Systemin is the first reported extracellular peptide that induces defense signaling in plants. It was purified from tomato leaf extracts using HPLC based on its proteinase inhibitor (PIN) gene-inducing activity (Pearce et al., 1991). Systemin is an 18-amino acid peptide processed from a 200-amino acid precursor named “prosystemin” (Pearce et al., 1991; Beloshistov et al., 2018). Genes encoding well-conserved prosystemins were identified in the Solanaceae species tomato, potato (Solanum tuberosum), bell pepper (Capsicum annuum), and black nightshade (Solanum nigrum), but not in tobacco (McGurl et al., 1992; Constabel et al., 1998). The tomato prosystemin gene is constitutively expressed throughout the plant except in the roots, and is further induced by wounding (McGurl et al., 1992). The prosystemin protein accumulates in the cytosol and nucleus of vascular parenchyma cells in response to wounding and methyl JA (MeJA) treatment (Narvíez-Vásquez and Ryan, 2004). Prosystemin does not carry an N-terminal signal sequence and, upon cell damage, is expected to passively leak into the apoplast where it is processed by phytaspases and possibly Leu aminopeptidase A (Ryan and Pearce, 1998; Beloshistov et al., 2018). Systemin is highly active. When supplied to the cut stems of young tomato plants, ∼40 fmol of systemin per plant is sufficient to induce half-maximal accumulation of two wound-inducible PINs that break the activity of digestive enzymes in the insect midgut (Green and Ryan, 1972; Pearce et al., 1991). Overexpression of the prosystemin gene leads to constitutive synthesis of the PINs (McGurl et al., 1994). Although exogenously supplied systemin moves systemically, systemin may not be the mobile signal mediating systemic wound responses. Grafting experiments with tomato JA biosynthesis and recognition mutants indicated that systemic wound signaling requires both biosynthesis of JA at the wound site and recognition of a JA signal in remote tissues, suggesting that JA controls the production of or acts as the mobile wound signal (Li et al., 2002b). It was proposed that systemin promotes systemic wound signaling by augmenting JA biosynthesis in the vascular tissues (Schilmiller and Howe, 2005). Identification of the receptor of systemin was a daunting task. A 160-kD systemin-binding protein named SR160 was initially purified from plasma membranes of tomato suspension cells using a photoaffinity analog of systemin (Scheer and Ryan, 2002). SR160 turned out to be the tomato homolog of the steroid hormone brassinolide receptor BRI1 (Scheer and Ryan, 2002; Scheer et al., 2003). Later studies indicated that, although SR160 increases binding of systemin to tobacco plasma membranes, it does not mediate systemin-triggered defense responses (Holton et al., 2007; Lanfermeijer et al., 2008; Malinowski et al., 2009). Two distinct LRR-RKs termed SYSTEMIN RECEPTOR1 (SYR1) and SYR2 were recently identified as the bona fide systemin receptors (Wang et al., 2018b). Tobacco leaves expressing SYR1 and SYR2 respond with an EC50 of ∼0.03 and >30 nm systemin based on systemin-induced ROS production, respectively (Wang et al., 2018b). Importantly, systemin is unable to induce production of ET and expression of the PIN gene PIN1 in tomato mutant lines lacking functional SYR1 and SYR2 (Wang et al., 2018b). Surprisingly, mechanical wounding still induces local and systemic expression of the PIN1 gene, even though tomato plants expressing a prosystemin antisense gene accumulate <40% of the wild-type level of PIN1 (McGurl et al., 1992; Wang et al., 2018b). Nevertheless, both the prosystemin antisense lines and the receptor mutant line support significantly better herbivore larval growth than wild type (McGurl et al., 1992; Wang et al., 2018b), demonstrating that systemin signaling contributes to resistance against insect herbivores in tomato. Plant Elicitor Peptides—Pep Receptor1/Pep Receptor2 The first plant elicitor peptide, Pep1, was isolated as a 23-amino acid peptide from extracts of Arabidopsis leaves, which is derived from the C terminus of a 92-amino acid precursor protein encoded by the PROPEP1 gene (Huffaker et al., 2006). The PROPEP1 protein does not carry an N-terminal signal peptide (Huffaker et al., 2006). It has been shown that PROPEP1 is processed by Ca2+-dependent type-II metacaspases in Arabidopsis (Hander et al., 2019; Shen et al., 2019). The Arabidopsis genome carries eight PROPEP genes, PROPEP1 to PROPEP8 (Huffaker et al., 2006; Bartels et al., 2013). PROPEP1, PROPEP2, PROPEP3, PROPEP5, and PROPEP8 are expressed in the roots and slightly in the leaf vasculature, and are inducible by wounding, and expression of PROPEP4 and PROPEP7 is restricted to the root tip and is not inducible by wounding (Bartels et al., 2013). Expression of PROPEP1, PROPEP2, and PROPEP4 is inducible by MeJA, whereas that of PROPEP2 and PROPEP3 is inducible by methyl SA (Huffaker and Ryan, 2007). PROPEP2 and PROPEP3 are also inducible by pathogen attacks and elicitors derived from pathogens (Huffaker et al., 2006). Furthermore, expression of PROPEP1 is strongly induced by Pep1 to Pep3, PROPEP2 and PROPEP3 are strongly induced by Pep1 to Pep6, PROPEP4 and PROPEP5 are weakly inducible, and PROPEP6 is not inducible by the peptides (Huffaker et al., 2006; Huffaker and Ryan, 2007; Yamaguchi et al., 2010). Interestingly, while PROPEP3-YFP is localized in the cytoplasm, PROPEP1-YFP and PROPEP6-YFP are associated with the tonoplast (Bartels et al., 2013). The different gene expression patterns and localization suggest nonredundant roles among the members of the PROPEP family. Based on the responses of PROPEP gene promoters to various stimuli, PROPEP genes were classified into four groups, with PROPEP1 in the first group, PROPEP2 and PROPEP3 in the second group, PROPEP4, PROPEP7, and PROPEP8 in the third group, and PROPEP5 in the fourth group (Safaeizadeh and Boller, 2019). Nevertheless, all Peps, when applied exogenously, activate MPK3 and MPK6, induce ET production, and inhibit seedling growth (Bartels et al., 2013). Exogenous Peps also induce expression of several defense genes including PDF1.2, MPK3, and WRKY33, production of ROS, elevation of cytosolic [Ca2+], and resistance to the bacterial pathogen Pst DC3000 (Huffaker et al., 2006; Qi et al., 2010; Yamaguchi et al., 2010). Pep1 also induces resistance against B. cinerea (Liu et al., 2013). Overexpression of PROPEP1 and PROPEP2 in Arabidopsis results in constitutive PDF1.2 expression and/or resistance against a root oomycete pathogen Pythium irregulare (Huffaker et al., 2006). The first PEPR, an LRR-RK called “PEPR1,” was purified from Arabidopsis suspension cells using a photoaffinity analog of Pep1, 125I1-Tyr-Pep1 (Yamaguchi et al., 2006). 125I1-Tyr-Pep1 is as active as Pep1 and binds to Arabidopsis suspension cells with a Kd of ∼0.25 nm (Yamaguchi et al., 2006). The second PEPR, PEPR2, was identified by phylogenetic analysis and searching for the most closely related gene to PEPR1 (Yamaguchi et al., 2010). Transgenic tobacco cells expressing PEPR1 and PEPR2 bind 125I1-Tyr-Pep1 with Kd values of 0.56 and 1.25 nM, respectively. PEPR1 and PEPR2 also bind Pep2 to Pep6 and Pep2, respectively (Yamaguchi et al., 2010). Both PEPRs carry a guanylyl cyclase (GC) catalytic domain with residues for catalysis being conserved (Qi et al., 2010; Yamaguchi et al., 2010), and the GC activity of PEPR1 has been experimentally demonstrated (Qi et al., 2010). It has been shown that Pep1 induces rapid formation of a heterocomplex containing de novo phosphorylated BAK1 and an ∼160-kD polypeptide that is expected to be PEPR1 (Schulze et al., 2010), while Pep2 induces PEPR1 association with BAK1, BAK1-LIKE1, SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE1 (SERK1), and SERK2 in Nicotiana benthamiana (Yamada et al., 2016). Consistently, the kinase domains of PEPR1 and PERP2 interact with that of BAK1 in yeast (Postel et al., 2010), and disruption of BAK1 sensitizes PEPR signaling (Yamada et al., 2016). The kinase domain of PEPR1 also interacts with and directly phosphorylates the receptor-like cytoplasmic kinase BOTRYTIS-INDUCED KINASE1 (BIK1) and BIK is required for Pep1-induced resistance against B. cinerea (Liu et al., 2013). Expression of PEPR1 and PEPR2 is inducible by wounding, MeJA, most Peps, and PAMPs such as flg22 (a 22-amino acid peptide corresponding to the N terminus of bacterial flagellin) and elf18 (Yamaguchi et al., 2010). It appears that PEPR1 is inducible in different parts of the plant, whereas PEPR2 induction is restricted to the root (Safaeizadeh and Boller, 2019). Pep-induced expression of defense genes including MPK3 and WRKY33 is partially suppressed in the pepr1 and pepr2 single mutants, and completely blocked in the pepr1 pepr2 double mutant (Yamaguchi et al., 2010). Pep1-induced expression of PR1 and PDF1.2 as well as resistance against Pst DC3000 are also compromised in the double mutant (Yamaguchi et al., 2010). Interestingly, ET-induced expression of defense genes and resistance to B. cinerea are also compromised in the pepr1 pepr2 double mutant (Liu et al., 2013). Furthermore, local application of Pep2 activates both JA and SA signaling pathways and resistance to Colletotrichum higginsianum path-29 strain in systemic leaves, although Pep2 may not be a mobile signal (Ross et al., 2014). In agreement with this result, biological induction of SAR is compromised in the pepr1 pepr2 mutant (Ross et al., 2014). RAPID ALKALINIZATION FACTORs—FERONIA RAPID ALKALINIZATION FACTOR (RALF) peptides were first isolated from tobacco, tomato, and alfalfa (Medicago sativa) leaves based on their activity in alkalinating the medium of tobacco suspension cells (Pearce et al., 2001b), and later from sugarcane (Saccharum) leaves using a similar approach (Mingossi et al., 2010). The tobacco RALF is a 49-amino acid peptide located at the C terminus of a 115-amino acid preproprotein. The preproprotein carries an N-terminal signal peptide and the derived RALF peptide contains four cysteines that form two disulfide bridges important for its activity (Pearce et al., 2001b). Later studies indicated that many, but not all, RALF preproproteins are cleaved at a conserved dibasic site RRXL by plant subtilisin-like Ser proteases such as the Arabidopsis SITE-1 PROTEASE/SBT6.1 (Matos et al., 2008; Srivastava et al., 2009; Stegmann et al., 2017). A photoaffinity analog of the tomato RALF peptide, 125I-azido-LeRALF, which has biological activity similar to the native LeRALF, binds to tomato suspension cells with a Kd of 0.8 nm (Scheer et al., 2005). A highly conserved YISY motif located at positions 5 through 8 from the N terminus is essential for RALF activity, presumably being required for productive binding to its putative receptor (Pearce et al., 2010b). RALF proteins have been identified in a large number of plant species that represent a variety of land plant lineages (Cao and Shi, 2012; Murphy and de Smet, 2014). The Arabidopsis genome carries 39 RALF genes (Sharma et al., 2016). Comprehensive analysis of the identified 795 RALF proteins from various plant species revealed four major clades. Clades I, II, and III carry the features important for RALF activity, including the RRXL cleavage site and the YISY motif important for receptor binding, whereas clade IV is highly diverged and lacks these features (Campbell and Turner, 2017). While the mean length of the RALF proteins in clades I, II, and III is 125 amino acids, the clade-IV RALFs have an average length of only 88 amino acids, suggesting that the members in clade IV may not be true RALFs (Campbell and Turner, 2017). RALF peptides were initially found to suppress root growth of tomato and Arabidopsis seedlings as well as tomato pollen tube growth (Pearce et al., 2001b; Covey et al., 2010). In line with these results, silencing of the tobacco RALF gene leads to increased root growth and abnormal root hair development (Wu et al., 2007), whereas transgenic overexpression of the Arabidopsis RALF1 and RALF23 genes results in dwarf phenotypes (Matos et al., 2008; Srivastava et al., 2009). Moreover, RALF genes are highly expressed in roots, shoots, and flowers (Zhang et al., 2010; Cao and Shi, 2012; Campbell and Turner, 2017). Collectively, these results support a role for RALF peptides in plant growth and development. On the other hand, the fungal pathogen Fusarium oxysporum f. sp. ciceri (Race 1)-induced expression of a RALF-related EST is 5-fold higher in resistant chickpea (Cicer arietinum) plants than in a susceptible variety (Gupta et al., 2010). In Arabidopsis, RALF8 is induced by a combination of water deficit and nematode stress, and overexpression of RALF8 confers susceptibility to drought stress and nematode infection (Atkinson et al., 2013). Moreover, synthetic RALF17 peptide increases resistance to Pst DC3000, while RALF23 reduces resistance to Pst DC3000 (Stegmann et al., 2017). Consistently, overexpression of RALF23 inhibits resistance to Pst DC3000 coronatine-minus, whereas loss of RALF23 enhances resistance to Pst DC3000 coronatine-minus (Stegmann et al., 2017). Interestingly, genomes of 26 species of phytopathogenic fungi encode RALF homologs, and the predicted F. oxysporum RALF appears to contribute to the virulence of the pathogen in tomato plants (Masachis et al., 2016; Thynne et al., 2017). These data together suggest potential involvement of RALFs in plant immunity. The first RALF receptor FERONIA (FER), a Catharanthus roseus receptor-like kinase1-like (CrRLK1L) receptor, was identified by quantitative phosphoproteomic profiling of RALF1-treated Arabidopsis seedlings (Haruta et al., 2014). The finding that the abundance of FER phosphopeptides increased in RALF1-treated samples led to the hypothesis that FER might be the receptor of RALF1. This hypothesis was supported by reduced RALF1 sensitivity of fer mutants and binding of RALF1 to FER (Haruta et al., 2014). Recent studies have shown that RALF4 and RALF19 bind to other CrRLK1L receptors including ANXUR1, ANXUR2, Buddha’s Paper Seal1, and Buddha’s Paper Seal2, as well as LEU-RICH REPEAT EXTENSIN proteins in regulating pollen tube integrity and sperm release in Arabidopsis (Mecchia et al., 2017; Ge et al., 2017). FER is also a receptor of RALF23 and perhaps RALF33 as well (Stegmann et al., 2017). Interestingly, FER constitutively associates with both FLS2 and BAK1 to act as scaffolds for ligand-induced FLS2-BAK1 complex formation. The constitutive association between BAK1 and FER can be strongly enhanced upon treatment with flg22, whereas binding of RALF23 to FER inhibits flg22/elf18-induced complex formation between FLS2/EFR and BAK1, leading to attenuation of FLS2/EFR-mediated PTI signaling (Stegmann et al., 2017). Furthermore, the GPI-anchored protein LORELEI-like GPI-AP1 (LLG1) constitutively associates with both FER and FLS2 and is required for PTI signaling (Li et al., 2015; Shen et al., 2017). LLG1 and the related LLG2 directly bind RALF23 to nucleate the assembly of a RALF23–LLG1/2–FER heterocomplex (Xiao et al., 2019), suggesting that RALFs may be perceived by distinct CrRLK1L receptor kinase-LLG/LRE heterocomplexes in regulating various biological processes including plant immunity. Phytosulfokines—Phytosulfokine Receptor1/Phytosulfokine Receptor2 Phytosulfokines (PSKs) are sulfated Tyr-containing pentapeptides with mitogenic activity in vitro. The first PSK was purified from conditioned medium of rapidly growing asparagus (Asparagus officinalis) cell cultures by following its mitogenic activity (Matsubayashi and Sakagami, 1996). Based on the amino acid sequence of the asparagus PSK, rice and Arabidopsis PSK genes were subsequently identified (Yang et al., 1999, 2001; Matsubayashi et al., 2006). PSKs are derived from ∼77- to 89-amino acid prepropeptide precursors through tyrosylprotein sulfotransferase (TPST)-mediated Tyr sulfation and subtilisin-like Ser protease-catalyzed proteolytic cleavage (Srivastava et al., 2008; Komori et al., 2009). The PSK precursors carry N-terminal signal sequences and are sulfated in the Golgi apparatus, secreted, and cleaved in the extracellular milieu (Yang et al., 1999, 2001; Srivastava et al., 2008; Komori et al., 2009). PSK binds to plasma membrane-enriched fractions with both high and low affinities (Kd values ranging from 1 to 100 nm; Matsubayashi et al., 1997; Matsubayashi and Sakagami, 1999). Photoaffinity cross-linking analysis indicated that the putative receptors for PSK in rice are 120- and 160-kD glycosylated proteins (Matsubayashi and Sakagami, 2000). The first PSK receptor, an LRR-RK, was purified from microsomal fractions of carrot suspension cells using ligand-based affinity chromatography, and the carrot PSK receptor (PSKr) gene encodes both 120- and 150-kD proteins (Matsubayashi et al., 2002). Amino acid homology search revealed that the Arabidopsis genome encodes two PSKRs, PSKR1 and PSKR2 (Matsubayashi et al., 2006; Amano et al., 2007). Structure analysis indicated that PSK interacts with and stabilizes an island domain of PSKR, which enhances PSKR heterodimerization with a SERK coreceptor (Wang et al., 2015). The cytoplasmic domain of PSKR1 has not only kinase activity but also GC activity. Both exogenous PSK treatment and overexpression of PSKR1 increase cGMP levels in protoplasts (Kwezi et al., 2011). Moreover, PSKR1, BAK1, CNGC17, and H+-ATPases AHA1 and AHA2 form a complex in mediating PSK-triggered signaling (Ladwig et al., 2015). PSK was initially shown to induce the proliferation of asparagus suspension cells (Matsubayashi and Sakagami, 1996; Matsubayashi et al., 1997). PSK precursors are constitutively secreted by suspension cells, and overexpression and silencing of PSK genes led to increased and reduced PSK levels in conditioned media of rice transgenic cells, respectively (Yang et al., 1999, 2001). PSK genes are stably expressed not only in suspension cells but also in intact plants (Yang et al., 1999, 2001). Overexpression of PSK genes resulted in enlarged transgenic calli (Yang et al., 2001; Matsubayashi et al., 2006). Similarly, transgenic carrot cells expressing high levels of sense mRNA of the PSK receptor exhibited accelerated proliferation, whereas those expressing antisense showed substantially reduced callus growth (Matsubayashi et al., 2002). Individual cells of the Arabidopsis pskr1-1 mutant gradually lose their potential to form calli as the tissues mature, while PSKR1-overexpressing plants exhibit significantly greater callus-forming potential than wild type (Matsubayashi et al., 2006). Genes encoding PSK precursors, processing enzymes, and/or receptors are inducible by wounding, elf18, flg22, and B. cinerea (Srivastava et al., 2008; Igarashi et al., 2012; Hou et al., 2014; Zhang et al., 2018), suggesting a potential involvement of PSK-PSKR signaling in plant immunity. Indeed, elf18-triggered immune responses are enhanced in the Arabidopsis pskr1–3 mutant (Igarashi et al., 2012). Mutations of the PSKR1 and TPST genes enhance resistance to Pst DC3000 and increase susceptibility to A. brassicicola, whereas overexpression of PSK2, PSK4, and PSKR1 leads to opposite effects (Mosher et al., 2013). However, overexpression of the rice PSKR1 gene activates SA signaling and enhances resistance to the bacterial pathogen Xanthomonas oryzae pv. oryzicola (Yang et al., 2019). Furthermore, exogenous application of PSK enhances Pst DC3000 growth in the Arabidopsis tpst-1 mutant (Mosher et al., 2013), and increases resistance to Botrytis cinerae in tomato (Zhang et al., 2018). In addition, silencing of the tomato PSKR1 gene enhances susceptibility to B. cinerae (Zhang et al., 2018). Binding of PSK to tomato PSKR1 elevates cytosolic [Ca2+], which enhances interaction between calmodulins and auxin biosynthetic YUCCAs, resulting in auxin-dependent immunity against B. cinerae (Zhang et al., 2018). GRIM REAPER Peptide—POLLEN-SPECIFIC RLK5 GRIM REAPER (GRI) belongs to a small family with six members in Arabidopsis. Its C-terminal Cys-rich domain is highly homologous to STIGMA-SPECIFIC PROTEIN1 that functions in regulation of exudate secretion in the pistils and promotion of pollen tube growth (Verhoeven et al., 2005; Huang et al., 2014). The GRI protein is 169-amino acids long, carries a predicted N-terminal signal peptide (amino acids 1–30), and is secreted into the apoplast (Wrzaczek et al., 2009). As the GRI gene expression in flowers is 1,000-fold higher than in leaves (Wrzaczek et al., 2009), GRI likely plays a role in reproduction. Indeed, a gain-of-function gri mutant and GRI-overexpressing plants exhibit reduced seed content in the siliques (Wrzaczek et al., 2009). Interestingly, the low basal GRI expression in leaves is inducible by ozone exposure and both gri and GRI-overexpressing plants are sensitive to ozone (Wrzaczek et al., 2009). The gri mutant is also resistant to the virulent bacterial pathogen Pst DC3000 (Wrzaczek et al., 2009). These gri phenotypes are likely caused by accumulation of a GRI peptide (GRIp) corresponding to the N-terminal variable region after the signal peptide (amino acids 31–96; Wrzaczek et al., 2015). Exogenous GRIp31–96 induces superoxide- and SA-dependent ion leakage, an indicator of cell death. GRI is cleaved by an apoplast-localized type II metacaspase METACASPASE9, releasing an 11-amino acid peptide, GRIp68–78, which is sufficient for induction of ion leakage (Wrzaczek et al., 2015). GRIp-induced ion leakage depends on the atypical LRR-RK, POLLEN-SPECIFIC RECEPTOR-LIKE KINASE5 (PRK5; Wrzaczek et al., 2015). Full-length GRI without the signal peptide and GRIp31–96 interact with the extracellular domain of PRK5 in vitro. A radiolabeled GRIp, 125I-Y-GRIp68–78, which is active for ion leakage induction, binds to Arabidopsis membrane extracts with a Kd of 1.9 nM. Binding of 125I-Y-GRIp68–78 to membrane extracts is reduced to background levels in prk5 mutants (Wrzaczek et al., 2015). These results support that PRK5 is a receptor of GRIp. However, because the prk5 and mc9 mutations have no significant effects on extracellular superoxide-induced ion leakage and resistance to Pst DC3000 (Wrzaczek et al., 2015), whether GRIp is a bona fide DAMP requires further investigation. PAMP-INDUCED SECRETED PEPTIDE1—RLK7 Genes encoding PAMP-INDUCED SECRETED PEPTIDE (PIP) precursors named prePIP1, prePIP2, and prePIP3 were identified by searching flg22- and elf18-induced transcription data (Hou et al., 2014). Eleven prePIP homologs were identified in Arabidopsis based on the highly conserved C-terminal sequences. All of the prePIP family members carry a N-terminal signal peptide (Hou et al., 2014; Vie et al., 2015). Orthologs of prePIPs were also identified in multiple other plant species such as soybean (Glycine max), grape (Vitis vinifera), maize, and rice (Hou et al., 2014). The prePIP1 gene is induced not only by PAMPs but also by methyl SA, Pst DC3000, and the fungal pathogen F. oxysporum f. sp. conglutinans strain 699 (Foc 699; Hou et al., 2014). Overexpression of prePIP1 and prePIP2 inhibits root growth and enhances resistance to Foc 699. Synthetic PIP1 and PIP2 comprising the conserved C terminus also inhibit root growth and induce immune responses similar to PTI (Hou et al., 2014). Interestingly, PIP1- and PIP2-mediated root growth inhibition and immune responses are compromised in transferred DNA insertion mutants of the RLK7 gene, which encodes a class XI LRR-RK, suggesting that RLK7 is a potential receptor of these PIPs (Hou et al., 2014). Indeed, RLK7-HA was pulled down with PIP1-biotin–associated streptavidin beads from membrane extracts of transgenic Arabidopsis plants expressing RLK7-HA, and specific binding of radiolabeled 125I-Y-PIP1 was detected in homogenates of tobacco leaves transiently expressing RLK7-HA in photoaffinity labeling assays, indicating that PIP1 directly binds to RLK7 (Hou et al., 2014). Moreover, PIP1-induced root growth inhibition and/or ROS production are reduced in the bak1-4 mutant but not in the bik1 mutant, indicating that PIP1-RLK7 signaling is partially dependent on BAK1, but independent of BIK1 (Hou et al., 2014). Finally, both PIP1 and PEP1 induce the expression of PrePIP1, ProPEP1, RLK7, PEPR1, and FLS2, suggesting that PIP1 and PEP1 function cooperatively in amplification of FLS2-initiated immune signaling (Hou et al., 2014). IDA-LIKE6 Peptide—HAESA/HAE-LIKE2 INFLORESCENCE DEFICIENT IN ABSCISSION (IDA) and IDA-LIKE (IDL) proteins are precursors of peptides that induce floral abscission (Butenko et al., 2003; Stenvik et al., 2008). The Arabidopsis IDA family has nine members (IDA and IDL1–8) characterized by an N-terminal signal peptide, a variable region, and a C-terminal conserved region where the PIP motif is located (Butenko et al., 2003; Stenvik et al., 2008; Vie et al., 2015). Genetic studies suggested that two LRR-RKs, HAESA (HAE) and HAE-LIKE2 (HSL2), are receptors of IDA/IDL-derived peptides (Stenvik et al., 2008). A chemiluminescent acridinium-labeled PIP with a Val residue at the N terminus and hydroxylation of the conserved Pro at position 7 termed “acri-PIPPo” binds to leaf materials of N. benthamiana expressing HSL2ƊKD with a Kd of ∼20 nm (Butenko et al., 2014), demonstrating that HSL2 is a bona fide receptor of IDA/IDL peptides. The IDA and IDL6 genes are upregulated by PAMPs, and IDL6 is also induced by Pst DC3000 (Hou et al., 2014; Wang et al., 2017b). Synthetic IDL6 and IDL7 extended PIP peptides downregulate the expression of a broad range of stress-responsive genes (Vie et al., 2017). Moreover, overexpression of IDL6 enhances susceptibility to Pst DC3000, whereas silencing of IDL6 increases resistance to the bacterial pathogen (Wang et al., 2017b). IDL6 elevates the transcription of Arabidopsis DEHISCENCE ZONE POLYGALACTURONASE2 (ADPG2), which encodes an active polygalacturonase that promotes pectin degradation to facilitate Pst DC3000 infection. Consistent with HAE and HSL2 being receptors of IDL6, IDL6-mediated ADPG2 expression and Pst DC3000 susceptibility are completely suppressed in the hae hsl2 double mutant (Wang et al., 2017b). Interestingly, the IDA-HEA/HSL2 ligand-receptor pair is required for P. syringae type III effector-triggered leaf abscission, which likely represents a new form of plant immunity (Patharkar et al., 2017). CONCLUSIONS AND FUTURE PERSPECTIVES A large and compelling body of evidence has accumulated in recent years, which supports an important role for DAMPs in plant immune responses (Fig. 1). Nevertheless, the identity of DAMPs in plants remains to be unambiguously defined. The Danger model postulates that healthy cells or cells undergoing normal physiological death do not generate danger signals (Matzinger, 1994, 2002). It was recently further argued in animals that a canonical DAMP can be upregulated, but not released, in response to PAMP detection or stress stimuli that presumably lead to necrosis (Martin, 2016). In plants, however, it seems that some DAMPs are actively released upon PAMP detection or environmental stresses (Deng et al., 2015; Chen et al., 2017). Release of DAMPs in the absence of cell death appears to be inconsistent with the Danger model. However, before we arrive at such a conclusion, we must consider the following possibilities. First, some DAMPs may play dual functions in plants. For instance, as in animals (Trautmann, 2009), eATP in plants not only acts as a DAMP in wound response, but also plays a major role in growth control (Choi et al., 2014b; Roux, 2014). The constitutive eATP and actively released ATP may be crucial for cell viability and growth changes (Chivasa et al., 2005; Liu et al., 2012; Deng et al., 2015). Second, the amount of DAMPs actively released may not be sufficient for immune activation. For example, in response to cold stress (4°C for 7 d), the concentration of eATP in the extracellular root medium of 7-d–old Arabidopsis seedlings is ∼8 nM, whereas that in the fluid released at the sites of physical wounding is ∼40 μm (Choi et al., 2014a; Deng et al., 2015). The eATP concentration under cold stress is likely too low to activate the eATP receptor DORN1 (Kd ∼46 n m) for wound response (Choi et al., 2014a). These results suggest that DAMPs may induce immune responses in a concentration-dependent manner, or there may be a threshold below which DAMPs do not activate immune response. Third, because plants lack specialized immune cells and adaptive immunity, cell-autonomous immunity may play a more important role in plants than in animals (Randow et al., 2013). Plants might have thus evolved mechanisms to actively release high amounts of DAMPs for activation of cell-autonomous immunity. Clearly, further investigations are required to determine whether sufficient DAMPs can be released in the absence of cell death for immune activation in plants. Regardless, even though the Danger model may need some modifications for the plant immune system, the general principles should be applicable. Figure 1. Open in new tabDownload slide Putative DAMP-receptor pairs and their functions in plant immunity. The cell surface receptor cartoons depict the putative DAMP receptors with their coreceptors or associated proteins. The cartoon for the Glu receptors GLR3.3/GLR 3.6 is based on an animal iGluR, a ligand-gated ion channel formed by four subunits. Each subunit has four domain layers: the extracellular N-terminal domain and ligand-binding domain, the transmembrane domain, and an intracellular C-terminal domain. For the sake of clarity, only two subunits are shown in the cartoon for GLR3.3/3.6. Moreover, although several RALFs including RALF17, RALF23, RALF33, and RALF34 are potential DAMPs that positively or negatively regulate immunity, RALF23 has been shown to bind LLG1/2 and FER to nucleate the assembly of RALF23-LLG1/2-FER heterocomplexes. Thus, only RALF23-LLG1/2-FER–mediated inhibition of PTI is presented here. Note that both LLG1 and FER are required for PTI signaling. In addition, although PIP1-induced–ROS production and root-growth inhibition partially depend on BAK1, whether the PIP1 receptor RLK7 interacts with BAK1 has not been reported. A question mark (?) is thus included in the RLK7/BAK1 cartoon to illustrate the uncertainty. Finally, dashed arrows are used to indicate the immune responses that are induced either by exogenously added DAMPs or by overexpression of the receptors; however, whether these immune responses are induced by the DAMPs through their receptors is unclear. By contrast, solid arrows represent immune responses that are activated by the DAMPs through their receptors. EGF, epidermal growth factor; IDL6p, INFLORESCENCE DEFICIENT IN ABSCISSION-LIKE6 peptide; INR, INCEPTIN RECEPTOR; SOBIR1, SUPPRESSOR OF BIR1-1; TM, transmembrane. Figure 1. Open in new tabDownload slide Putative DAMP-receptor pairs and their functions in plant immunity. The cell surface receptor cartoons depict the putative DAMP receptors with their coreceptors or associated proteins. The cartoon for the Glu receptors GLR3.3/GLR 3.6 is based on an animal iGluR, a ligand-gated ion channel formed by four subunits. Each subunit has four domain layers: the extracellular N-terminal domain and ligand-binding domain, the transmembrane domain, and an intracellular C-terminal domain. For the sake of clarity, only two subunits are shown in the cartoon for GLR3.3/3.6. Moreover, although several RALFs including RALF17, RALF23, RALF33, and RALF34 are potential DAMPs that positively or negatively regulate immunity, RALF23 has been shown to bind LLG1/2 and FER to nucleate the assembly of RALF23-LLG1/2-FER heterocomplexes. Thus, only RALF23-LLG1/2-FER–mediated inhibition of PTI is presented here. Note that both LLG1 and FER are required for PTI signaling. In addition, although PIP1-induced–ROS production and root-growth inhibition partially depend on BAK1, whether the PIP1 receptor RLK7 interacts with BAK1 has not been reported. A question mark (?) is thus included in the RLK7/BAK1 cartoon to illustrate the uncertainty. Finally, dashed arrows are used to indicate the immune responses that are induced either by exogenously added DAMPs or by overexpression of the receptors; however, whether these immune responses are induced by the DAMPs through their receptors is unclear. By contrast, solid arrows represent immune responses that are activated by the DAMPs through their receptors. EGF, epidermal growth factor; IDL6p, INFLORESCENCE DEFICIENT IN ABSCISSION-LIKE6 peptide; INR, INCEPTIN RECEPTOR; SOBIR1, SUPPRESSOR OF BIR1-1; TM, transmembrane. It is expected that multiple DAMPs would be released upon any type of cell damage. However, the combinations of DAMPs following different types of cell damages may be different. For instance, besides primary DAMPs, mechanical damage leads to release of wounding-induced secondary DAMPs such as systemin (Pearce, 2011), whereas pathogen attack results in release of pathogen-induced secondary DAMPs including Peps and PIPs (Huffaker et al., 2006; Hou et al., 2014). Moreover, DAMPs may be released at various times during plant-microbe interaction due to their different subcellular localizations. In this regard, DAMPs derived from the cell wall would be released early, followed by those from the cytoplasm, and finally from the nucleus. Additionally, the half-lives and apoplastic mobility of DAMPs as well as the activities of receptors for DAMPs may differ significantly (Adriouch et al., 2012). Thus, DAMPs should function cooperatively with each other, as well as with PAMPs in a temporal, spatial, and stress-specific manner to generate a peculiar immune response. Determining the role of DAMPs in plant immune responses is an important but challenging task (see Outstanding Questions). Several studies have investigated the interplays between DAMPs and PAMPs (such as flg22 and elf18) as well as between different DAMPs. Both synergism and antagonism between DAMPs and PAMPs/DAMPs have been observed (Fauth et al., 1998; Stennis et al., 1998; Aslam et al., 2009; Ma et al., 2012; Flury et al., 2013; Tintor et al., 2013; Stegmann et al., 2017). However, because DAMPs are released during pathogen infection or herbivore attack, the context is extremely complex. It would be difficult to sort out the contribution of individual DAMPs to the final specific immune phenotype. Perhaps something similar to the recently proposed PAMP/DAMP combination-based “inflammatory code” could help solve this puzzle (Escamilla-Tilch et al., 2013). Moreover, although evidence supporting a role for DAMPs in effector-triggered immunity is accumulating (Ma et al., 2012; Zhang and Mou, 2012), in-depth investigations are warranted. In addition, several DAMPs have been implicated in systemic responses including SAR (Pearce et al., 1991; Ross et al., 2014; Toyota et al., 2018; Wang et al., 2019a), suggesting that DAMP signaling is an integral component of biological induction of systemic responses. Future research should investigate whether DAMPs move systemically or act through other signal molecules similarly to systemin (Li et al., 2002b; Schilmiller and Howe, 2005), and how the DAMP signal is transduced into the nucleus. Open in new tabDownload slide Open in new tabDownload slide It is worth mentioning that what we currently know about DAMPs is just the tip of the iceberg. Among the countless numbers of intracellular molecules, many could potentially become DAMPs if released into the apoplast. Furthermore, a recent study using a bioinformatics approach identified >1,000 putative secreted peptides in Arabidopsis (Lease and Walker, 2006), not to mention other plant species with larger genomes than Arabidopsis. Many of the putative peptides could potentially function as DAMPs. Identification of potential new DAMPs as well as the processing enzymes and/or receptors for the candidate DAMPs would greatly improve our understanding of plant DAMP signaling and the plant immune system as a whole. It is expected that a deeper understanding of plant DAMPs and the plant immune system could significantly help design new strategies to breed crop varieties with increased resistance against pathogens and/or herbivores. ACKNOWLEDGMENTS We apologize to researchers whose relevant studies were not cited in this review due to page limitations, and would like to thank Fiona M. Harris for careful reading of the article. 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