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Role of autophagy during plant-virus interactions
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Role of autophagy during plant-virus interactions Asigul Ismayil, Meng Yang, Yule Liu* Center for Plant Biology, Tsinghua-Peking Joint Center for Life Sciences, MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China
ARTICLE INFO
ABSTRACT
Keywords: Autophagy Plant Virus Immunity Defense Counter-defense
Autophagy is an essential and conserved cellular degradation pathway in eukaryotes. In metazoans, autophagy is highly engaged during the immune responses through interfacing either directly with intracellular pathogens or indirectly with immune signaling molecules. Recent studies have demonstrated that autophagy plays important roles in regulating immunity-related cell death, antiviral and promoting viral pathogenesis during plant-virus interactions. In this review, we will summarize latest progresses and discuss the significant roles of autophagy in the defense and counter-defense arm race between host plants and viruses.
1. Introduction Plant viruses are one of the most economical devastating microorganisms that leading to crop losses and serious threats to food security. In response to viral infection, plants have evolved the multilayered antiviral mechanisms including gene silencing [1] and resistance (R) gene-mediated resistance [2]. Recently, autophagy is reported to participate in plant-pathogen interaction [3]. Autophagy is an evolutionary conserved intracellular degradation pathway, by which cytoplasmic constituents, including proteins and dysfunctional organelles, delivered to lysosomes or vacuoles for degradation [4]. There are three major types of autophagy in eukaryotic cells: macroautophagy, microautopahgy, and chaperone-mediated autophagy (CMA) [5,6]. Macroautophagy (hereafter referred to as autophagy) is mediated by a de novo-formed double-membrane vesicle, named autophagosome, then the outer membrane of mature autophagosome is fused with the lysosome (in mammals) or vacuole (in yeast and plants) to release the sequestered cargo for breakdown by vacuolar acid hydrolases [7,8]. Genes involved in autophagy processes are termed autophagy-related (ATG) genes. Among these, the essential genes for autophagosome formation are referred to as the core machinery genes [9]. One can distinguish the following key steps in the life cycle of an autophagosome: initiation, elongation, cargo uptake,
closure/maturation, and fusion with vesicles (including the lysosomes or vacuoles) followed by destruction of the cargos [10]. With the discovery of ATG-genes in yeast and mammal, autophagy has been found to link with many physiological processes including intracellular quality control, amino acid pool maintenance, cell differentiation and development, cell death, maintenance of cellular and tissue homeostasis, tumor suppression, and anti-aging [11]. In plants, autophagy is increasingly recognized for its central importance in development, reproduction, metabolism, hormone signaling, cell death, senescence, and responses to abiotic and biotic stresses [12,13]. In metazoans, autophagy plays a crucial role in adaptive and innate immunity against viruses [14]. In turn, many viruses have evolved measures to antagonize autophagy or even hijack autophagic constituents for viral replication, subversion of immune responses, and promoting host fitness during virus infection [15]. Some defense-related host factors are reported to be targeted by pathogens for autophagic degradation, thus enhancing pathogen virulence [16,17]. Recently, the direct interactions between autophagy and plant viruses have also begun to emerge. In this review, we focus on the roles of autophagy during plant-virus interaction.
Abbreviations: CAM, chaperone-mediated autophagy; ATG, autophagy-related gene; HR PCD, hypersensitive programmed cell death; TMV, tobacco mosaic virus; TEV, tobacco etch virus; CMV, cucumber mosaic virus; TAV, tomato aspermy virus; 3-MA, 3-methyladenine; GAPC, glyceraldehyde-3-phosphat dehydrogenase; CLCuMuV, Cotton leaf curl Multan virus; CLCuMuB, Cotton leaf curl Multan betasatellite; PE, phosphatidylethanolamine; VIGS, virus-induced gene silencing; CaMV, Cauliflower mosaic virus; TuMV, Turnip mosaic virus; BSMV, Barley stripe mosaic virus; HCpro, helper-component proteinase; RdRp, RNA-dependent RNA polymerase; CGMMV, Cucumber green mottle mosaic virus; PepMV, Pepino mosaic virus; VSRs, viral suppressors of RNA silencing; AGO1, ARGONAUTE1; SGS3, suppressor of gene silencing 3; vsiRNA, virus-derived small interfering RNA; VPg, viral genome-linked protein; CAM, calmodulin-like protein; BI-1, bax inhibitor 1 ⁎ Corresponding author. E-mail address: [email protected] (Y. Liu). https://doi.org/10.1016/j.semcdb.2019.07.001 Received 23 January 2019; Received in revised form 17 June 2019; Accepted 5 July 2019 1084-9521/ © 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Asigul Ismayil, Meng Yang and Yule Liu, Seminars in Cell and Developmental Biology, https://doi.org/10.1016/j.semcdb.2019.07.001
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2. Autophagy regulates programmed cell death during plant-virus interactions
compatible plant-virus interaction. Autophagy can directly target viruses or individual viral components for degradation in plants. Tobacco rgs-CaM (calmodulin-like protein) could bind to the positively charged domains of several viral RNA silencing suppressors (VRSs) including HC-Pro from tobacco etch virus (TEV), 2b proteins from cucumber mosaic virus (CMV) and tomato aspermy virus (TAV). A recent study showed that NtCaM could mediate degradation of the dsRNA binding VSR 2b via the autophagy-like protein degradation pathway [27]. Indeed, either treatment with an autophagy inhibitor 3-MA or silencing of Beclin1/ATG6 impaired the degradation of CMV 2b protein [27]. These data suggest that autophagy could degrade VRS through plant rgs-CaM, although 3-MA has multiple off-target effects [28] and Beclin1/ATG6 also functions in vacuolar protein sorting, endosome-toGolgi retrograde transport or other pathways besides autophagy [29]. In addition, the in vitro application of an autophagy inhibitor wortmannin partially inhibit proteolysis of Tomato yellow leaf curl virus (TYLCV) proteins [30,31]. Further, autophagy genes are transcriptionally up-regulated by infection of some viruses in plants [32,33]. Recently, several studies provide clear evidences to prove that autophagy acts as an antiviral defense role against both DNA and RNA viruses in plants by targeting viral components for degradation [34–38]. Cotton leaf curl Multan virus (CLCuMuV) is a circular single-stranded DNA virus and associates with the disease-specific satellite DNA − Cotton leaf curl Multan betasatellite (CLCuMuB). CLCuMuB only encodes a single protein βC1, which is required for induction of disease symptoms and viral accumulation in plants [34]. Haxim et al. (2017) reported that autophagic machinery targeted and degraded viral βC1 through its interaction with the key autophagy protein ATG8 [34], which is conjugated with phosphatidylethanolamine (PE) and required for the autophagosome maturation in the autophagy pathway [39]. We found that βC1, but not its mutant βC1V32A, directly interacts with ATG8f. CLCuMuV infection activates autophagy and enhances the autophagic flux. Interestingly, disruption of autophagy by silencing of two ATG genes (ATG5 and ATG7) caused more severe leaf curl symptoms caused by CLCuMuV infection, increased the accumulation of viral DNA and βC1 protein whilst the enhanced autophagy by silencing of GAPC [20] impaired CLCuMuV infection. Furthermore, the mutant CLCuMuV carrying βC1V32A showed increased symptoms and viral DNA accumulation in plants [34]. In addition, autophagy is shown to have an antiviral defense against two additional geminiviruses including TYLCV and Tomato yellow leaf curl China virus (TYLCCNV) [34]. These data indicate that autophagy plays an antiviral role during geminiviral infection [34]. Cauliflower mosaic virus (CaMV) is a double-stranded DNA pararetrovirus [40]. Hafrén and colleagues (2017) showed that autophagy limited CaMV infection during its compatible interaction with Arabidopsis [38]. Severer symptoms were observed in the autophagy-deficient Arabidopsis mutants (atg5 and atg7) after the CaMV infection. Strikingly, the major structure protein P4 of CaMV capsid was specifically accumulated in the atg5 and atg7 mutant plants whilst other viral proteins did not show obvious difference [38]. Further, NBR1-mediated selective autophagy suppressed the accumulation of CaMV P4 and viral DNA at the cellular level [38]. These results suggest that autophagy targets viral capsid protein P4 and P4-assembled viral particles to mediate their degradation and restrict CaMV infection by NBR1-dependent manner [38]. Autophagy functions as an antiviral mechanism against not only plant DNA viruses but also plant RNA viruses. Turnip mosaic virus (TuMV) and Barley stripe mosaic virus (BSMV) are two plant positive single-stranded RNA viruses. Two reports showed that autophagy was induced by TuMV infection and restrict viral RNA accumulation [36,37]. Hafrén and colleagues (2018) found that the autophagy cargo receptor NBR1-dependent selective autophagy repressed viral accumulation by targeting the helper-component proteinase (HCpro), a viral suppressor of RNA silencing (VSR) [37]. Li et al. (2018) found that
During the incompatible plant-pathogen interactions, plant immunity is often associated with the hypersensitive response, a form of programmed cell death (HR PCD) at pathogen infection sites. Liu et al. (2005) first links plant immunity and PCD to autophagy [18]. Plant autophagy is induced by N-mediated resistance against tobacco mosaic virus (TMV) and this induction is dependent on host Beclin1 (an ortholog of the yeast and mammalian autophagy ATG6/VPS30). Meanwhile, we found that several ATG genes including Beclin1, PI3K/VPS43, ATG3, and ATG7 are required for limiting N-mediated HR PCD into TMV infection sites [18]. In addition, we also found that Beclin1 is required to limit HR PCD induced by another two resistance (R) genes (bacterial R gene Pto and fungal R gene Cf9) and two general pathogen elicitors (INF1 from Phytophthora infestans and P. syrinagae pv. DC3000). These findings suggest that autophagy negatively regulates plant immunity-related cell death in the tissues beyond pathogen infection sites [18]. The effect of autophagy on HR PCD at pathogen infection sites seems to be different from that on PCD beyond pathogen infection areas. Hofius et al. (2009) discovered that autophagy could contribute to HR PCD in a pro-death way. In Arabidopsis, atg knockout mutants atg7 and atg9 showed a delayed HR PCD induced by Pst DC3000 (avrRPS4) infection [19]. In addition, Han et al. (2015) reported that cytoplasmic glyceraldehyde-3-phosphat dehydrogenases (GAPCs) interacts with ATG3 directly and negatively regulates autophagy. Silencing of GAPCs enhanced N-mediated local plant resistance against TMV and HR cell death [20]. Furthermore, Xu et al. (2017) found that plant Bax inhibitor-1 (BI-1) interacted with the core autophagy-related protein ATG6/Beclin1 and positively regulated autophagy [21]. Silencing of BI-1 compromised autophagy induced by N-mediated resistance to TMV and enhanced Nmediated HR PCD. On the contrary, overexpression of BI-1 increased autophagic activity and enhanced defense to viral infection. Interestingly, the overexpressed BI-1 also caused autophagy-independent cell death in a dose-dependent manner, which suggest that autophagy plays both pro-survival and pro-death roles in nature [21]. Both PCD and ROS are involved in plant defense against virus infection [22–25]. Recently, it was reported that ROS level and PCD progress were both regulated by autophagy during the compatible plant-virus interaction. TMV local-infection on tomato leaves not only caused the PCD in the distal root tissues but also induced autophagy in root-tip cells [26]. The intracellular ROS induced by TMV infection wasexcreted into the cell wall and intercellular layer, which is accompanied with the enhanced expression of several ATG genes (ATG8, ATG5, ATG7, and ATG10). Interestingly, treatment with autophagy inhibitor 3-methyladenine (3-MA) caused an elevated systemic PCD process in the root-tip cells but did not affect the ROS level in the apical tissue, suggesting that ROS, as a signaling molecule, can trigger autophagy to eliminate the excessive intracellular ROS oxidative damage and maintain cell survival to limit viral infection [26]. 3. Autophagy functions as an antiviral mechanism against plant viruses Autophagy has been analyzed in mammals as a recognized player during host immune response for defensing diverse pathogens, such as viruses. First report of the effect of autophagy on plant defense against virus is derived from the study on N-mediated TMV resistance [18]. Silencing of several ATG genes (Beclin1, PI3K/VPS43, ATG3, and ATG7) enhanced TMV accumulation in the inoculated leaves but did not cause TMV spreading into systemic leaves in N-containing Nicotiana. benthamiana plants, suggesting that autophagy plays a role in local antiviral defense against TMV in N-mediated resistance against TMV. Recently, autophagy is found to play an important role in the 2
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Fig. 1. Role of autophagy during plant-virus interactions. Upper part indicates antiviral aspects of plant autophagy while autophagy manipulated by plant viral proteins shown in the bottom part. The names of virus families are illustrated in the interaction area respectively. (Upper panel) The viral suppressor of RNA silencing (VSR) protein 2b could undergo autophagic clearance by binding to rgsCaM. The VSR protein βC1 of geminivirus is degraded by autophagy by binding to ATG8. The capsid protein of caulimoviruses, P4, is a bona fide cargo of plant NBR1, thus cleared by selective autophagy. The GDD conserved motif-containing RdRps (NIb) is degraded through autophagy by binding with ATG6/Beclin1, a potential selective autophagy cargo receptor. (Lower panel) Evidence also exists that viruses can manipulates the autophagy to facilitate infection. RSV NSvc4 protein interferes with S-acylation of remorin and further induced its autophagic degradation to overcome remorin-mediated inhibition of virus movement. Viral P0 hijacks the SKP1-CUL-SCF ubiquitin-protein ligase to promote the degradation of AGO1. TuMV VPg protein interacts with SGS3 and could induce partial degradation of SGS3 by autophagy. VSR protein γb interact with the autophagy key factor ATG7 to disrupt the ATG7-ATG8 interaction to block autophagy, thus facilitates virus infection. CaMV P6 protein interrupts the interaction of NBR1 and P4 by inhibiting autophagy through some unknown way. VPg and 6k2 are found to block autophagy by the unknown way to accumulate the protein level of HCPro.
synthesis for virus-derived small interfering RNA (vsiRNA) production [50]. Viral genome-linked protein (VPg) encoded by TuMV interacted with SGS3 and induced the degradation of both SGS3 and its intimate partner RNA-dependent RNA polymerase 6 (RDR6). They discovered that VPg mediated degradation of SGS3 occurs via both the autophagy and 26S ubiquitin-proteasome pathways [51]. Harfen et al. (2017) proposed a model for the roles of autophagy in the CaMV infection cycle [38]. As autophagy cargo receptor, NBR1 targets viral capsid protein P4 and P4-assembled viral particles to mediate their degradation by autophagy, restricting CaMV infection. In contrast, CaMV P6 protein could disrupt the interaction between viral P4 and host NBR1 to protect viral replication factory inclusions from autophagic degradation [38]. In addition, virus-triggered autophagy also prevents extensive senescence and tissue death of infected plants in a largely NBR1-independent manner to facilitate viral particle acquisition by aphid vectors and CaMV transmission [38]. TuMV VPg and 6K2 proteins were found to antagonize antiviral capacity of NBR1-dependent autophagy by blocking NBR1 and HCpro degradation [37]. NBR1 accumulation might be affected by other viral proteins, indicating that other viral components might manipulate autophagy by some way. NBR1-independent bulk autophagy prevents premature plant death, thus promotes plant fitness to the benefit of virus production and potyvirus epidemiology [37]. Some viruses or viral factors also aff ;ect starch accumulation. For examples, TMV movement protein and BSMV γb protein induce starch accumulation [35,52]. Autophagy is reported to contribute to leaf starch degradation [53]. These viruses may inhibit autophagy to promote viral infection. Indeed, BSMV γb interferes with the interaction of ATG7 with ATG8 in a competitive manner to suppress autophagy for promoting viral infection [35]. NSvc4 protein of Rice stripe virus (RSV) is reported to interfere with S-acylation of Remorin and induced its autophagic degradation to overcome remorin-mediated inhibition of virus movement, thus facilitating virus infection [54] Li et al (2017) showed that the calmodulin-like protein rgs-CaM suppresses RNA silencing and promotes the infection of TYLCCNV by mediating degradation of SGS3 via autophagy [55]. In this study, silencing of NbBeclin1, NbPI3K, or NbVPS15 blocked the degradation of
Beclin1/ATG6, a core autophagy component, inhibited TuMV infection by its interaction to suppress and degrade viral RNA-dependent RNA polymerase (RdRp) [36]. TuMV NIb was targeted for Beclin1-mediated autophagic degradation likely through its interaction with Beclin1 and the autophagy adaptor protein ATG8a. Blocking autophagy by silencing either Beclin1 or ATG8a enhances NIb accumulation and promotes viral infection and vice versa. The interaction of Beclin1 with viral RdRp seems to be conserved, and extends to several RNA viruses including Cucumber green mottle mosaic virus and Pepino mosaic virus [36]. Thus, Beclin1 limits viral infection through suppression and also likely autophagic degradation of the viral RdRp. Yang et al. (2018) reported that autophagy also plays an antiviral defense against BSMV. Viral RNAs and proteins increased in ATG7- or ATG5-silenced plants compared with control plants [34–38] (Fig. 1, upper panel). 4. Autophagy is manipulated by plant viruses Apart from its antiviral defense, autophagy can also enhance the replication of some viruses in mammals [41–45]. Many viruses have evolved to escape or antagonize host autophagy in order to promote viral infection [15,46]. Viruses also exploit autophagy mechanisms for their own benefits [41–45]. In the course of plant-virus interactions, plants have evolved ingenious counter-attack mechanisms to diminish or eliminate invading viral pathogens. RNA silencing is a natural antiviral defense mechanism. For the effective infection, plant viruses encode VSRs to counteract host RNA silencing. Recent studies revealed that the VSR protein P0 from polerovirus triggered the degradation of ARGONAUTE1 (AGO1), a key component of RNA-induced silencing complex [47–49]. Viral P0, an F-box protein, hijacks the host S-phase kinase-associated protein1 (SKP1)-cullin1 (CUL1)-F-box protein (SCF) ubiquitin-protein ligase (E3) to promote ubiquitylation of AGO1. Interestingly, autophagy inhibitor treatment blocked AGO1 degradation. Further, AGO1 colocalized with ATG8a in the autophagic bodies [50]. These studies suggest that P0 triggers AGO1 degradation by the autophagy pathway. Cheng and his colleagues (2017) reported that TuMV infection reduced protein level of suppressor of gene silencing 3 (SGS3), a key component of the RNA silencing pathway that functions in double-stranded RNA 3
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SGS3 and inhibited TYLCCNV infection, suggesting that autophagy may be required for TYLCCNV infection [55]. However, silencing of ATG5 and ATG7 enhanced TYLCCNV infection [34]. Considered that PI3K complex (includes NbBeclin1, NbPI3K, or NbVPS15) functions in vacuolar protein sorting, endosome-to-Golgi retrograde transport or other pathways besides autophagy [29], it is possible that non-autophagy function of PI3K complex is required for TYLCCNV infection (Fig. 1, lower panel).
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5. Conclusions and perspectives Autophagy has emerged as a central part of plant defense against pathogens. This review highlights the importance of autophagy in plant-virus interactions. Although most papers have reported that autophagy acts as a positive regulator of defense against a wide range of plant pathogens [18,56,57], autophagy is also reported to promote pathogen invasion [54]. During the incompatible plant-virus interactions, autophagy prevents cells from death beyond viral infection sites. During the compatible plant-virus interactions, autophagy acts as an antiviral mechanism and mediates the degradation of viral components or particles, while plant viruses have evolved mechanisms to counteract or hijack autophagic processes to promote viral infection or virulence. In addition, autophagy may prevent senescence and tissue death of infected plants to promote plant fitness to the benefit of virus production and transmission [34]. Little is known about the mechanisms and the critical and perplexing role of autophagy in plant antiviral defense responses. Several viruses have been identified to modulate plant autophagy and viral infection can induce or block autophagy, depending on different plantvirus interactions. So far, it is still unclear what viral factor(s) is/are responsible for autophagy induction and which mechanisms pathways are involved in autophagy induction during plant-virus interactions. It is known that BSMV γb suppress autophagy by interacting with ATG7 to impair the interaction between ATG7 with ATG8 [35]. However, it is obscure how autophagy is suppressed during other plant-virus interactions. Selective autophagy cargo receptor NBR1/Joak2 is involved in plant antiviral defense against CaMV and TuMV [37]. Beclin1 is also thought as a selective autophagy cargo receptor to limit TuMV infection [36]. It is possible that more selective autophagy cargo receptors take part in plant antiviral immunity. Uncovering the molecular mechanism and role of autophagy in plant-virus interactions will help us to understand plant responses to viral infection. Manipulation of autophagy could provide the enhanced resistance to plant viruses. For example, silencing of GAPCs in transgenic plants will lead to increased defense against geminiviruses. Acknowledgements This work was supported by Ministry of Science and Technology of the People’s Republic of China (2017YFA0503401) and the National Natural Science Foundation of China (31530059 and 31421001). References [1] M. Incarbone, P. Dunoyer, RNA silencing and its suppression: novel insights from in planta analyses, Trends Plant Sci. 18 (7) (2013) 382–392. [2] K.K. Mandadi, K.G. Scholthof, Plant immune responses against viruses: how does a virus cause disease? Plant Cell 25 (5) (2013) 1489–1505. [3] S. Han, B. Yu, Y. Wang, Y. Liu, Role of plant autophagy in stress response, Protein Cell 2 (2011) 784–791. [4] D.J. Klionsky, P. Codogno, The mechanism and physiological function of macroautophagy, J. Innate Immun. 5 (5) (2013) 427–433. [5] D.J. Klionsky, The molecular machinery of autophagy: unanswered questions, J. Cell. Sci. 118 (Pt 1) (2005) 7–18. [6] A. Massey, R. Kiffin, A.M. Cuervo, Pathophysiology of chaperone-mediated autophagy, Int. J. Biochem. Cell Biol. 36 (12) (2004) 2420–2434. [7] N. Mizushima, B. Levine, A.M. Cuervo, D.J. Klionsky, Autophagy fights disease through cellular self-digestion, Nature 451 (7182) (2008) 1069–1075. [8] Y. Ohsumi, Molecular dissection of autophagy: two ubiquitin-like systems, Nat. Rev.
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Role of autophagy during plant-virus interactions Asigul Ismayil, Meng Yang, Yule Liu* Center for Plant Biology, Tsinghua-Peking Joint Center for Life Sciences, MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China
ARTICLE INFO
ABSTRACT
Keywords: Autophagy Plant Virus Immunity Defense Counter-defense
Autophagy is an essential and conserved cellular degradation pathway in eukaryotes. In metazoans, autophagy is highly engaged during the immune responses through interfacing either directly with intracellular pathogens or indirectly with immune signaling molecules. Recent studies have demonstrated that autophagy plays important roles in regulating immunity-related cell death, antiviral and promoting viral pathogenesis during plant-virus interactions. In this review, we will summarize latest progresses and discuss the significant roles of autophagy in the defense and counter-defense arm race between host plants and viruses.
1. Introduction Plant viruses are one of the most economical devastating microorganisms that leading to crop losses and serious threats to food security. In response to viral infection, plants have evolved the multilayered antiviral mechanisms including gene silencing [1] and resistance (R) gene-mediated resistance [2]. Recently, autophagy is reported to participate in plant-pathogen interaction [3]. Autophagy is an evolutionary conserved intracellular degradation pathway, by which cytoplasmic constituents, including proteins and dysfunctional organelles, delivered to lysosomes or vacuoles for degradation [4]. There are three major types of autophagy in eukaryotic cells: macroautophagy, microautopahgy, and chaperone-mediated autophagy (CMA) [5,6]. Macroautophagy (hereafter referred to as autophagy) is mediated by a de novo-formed double-membrane vesicle, named autophagosome, then the outer membrane of mature autophagosome is fused with the lysosome (in mammals) or vacuole (in yeast and plants) to release the sequestered cargo for breakdown by vacuolar acid hydrolases [7,8]. Genes involved in autophagy processes are termed autophagy-related (ATG) genes. Among these, the essential genes for autophagosome formation are referred to as the core machinery genes [9]. One can distinguish the following key steps in the life cycle of an autophagosome: initiation, elongation, cargo uptake,
closure/maturation, and fusion with vesicles (including the lysosomes or vacuoles) followed by destruction of the cargos [10]. With the discovery of ATG-genes in yeast and mammal, autophagy has been found to link with many physiological processes including intracellular quality control, amino acid pool maintenance, cell differentiation and development, cell death, maintenance of cellular and tissue homeostasis, tumor suppression, and anti-aging [11]. In plants, autophagy is increasingly recognized for its central importance in development, reproduction, metabolism, hormone signaling, cell death, senescence, and responses to abiotic and biotic stresses [12,13]. In metazoans, autophagy plays a crucial role in adaptive and innate immunity against viruses [14]. In turn, many viruses have evolved measures to antagonize autophagy or even hijack autophagic constituents for viral replication, subversion of immune responses, and promoting host fitness during virus infection [15]. Some defense-related host factors are reported to be targeted by pathogens for autophagic degradation, thus enhancing pathogen virulence [16,17]. Recently, the direct interactions between autophagy and plant viruses have also begun to emerge. In this review, we focus on the roles of autophagy during plant-virus interaction.
Abbreviations: CAM, chaperone-mediated autophagy; ATG, autophagy-related gene; HR PCD, hypersensitive programmed cell death; TMV, tobacco mosaic virus; TEV, tobacco etch virus; CMV, cucumber mosaic virus; TAV, tomato aspermy virus; 3-MA, 3-methyladenine; GAPC, glyceraldehyde-3-phosphat dehydrogenase; CLCuMuV, Cotton leaf curl Multan virus; CLCuMuB, Cotton leaf curl Multan betasatellite; PE, phosphatidylethanolamine; VIGS, virus-induced gene silencing; CaMV, Cauliflower mosaic virus; TuMV, Turnip mosaic virus; BSMV, Barley stripe mosaic virus; HCpro, helper-component proteinase; RdRp, RNA-dependent RNA polymerase; CGMMV, Cucumber green mottle mosaic virus; PepMV, Pepino mosaic virus; VSRs, viral suppressors of RNA silencing; AGO1, ARGONAUTE1; SGS3, suppressor of gene silencing 3; vsiRNA, virus-derived small interfering RNA; VPg, viral genome-linked protein; CAM, calmodulin-like protein; BI-1, bax inhibitor 1 ⁎ Corresponding author. E-mail address: [email protected] (Y. Liu). https://doi.org/10.1016/j.semcdb.2019.07.001 Received 23 January 2019; Received in revised form 17 June 2019; Accepted 5 July 2019 1084-9521/ © 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Asigul Ismayil, Meng Yang and Yule Liu, Seminars in Cell and Developmental Biology, https://doi.org/10.1016/j.semcdb.2019.07.001
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2. Autophagy regulates programmed cell death during plant-virus interactions
compatible plant-virus interaction. Autophagy can directly target viruses or individual viral components for degradation in plants. Tobacco rgs-CaM (calmodulin-like protein) could bind to the positively charged domains of several viral RNA silencing suppressors (VRSs) including HC-Pro from tobacco etch virus (TEV), 2b proteins from cucumber mosaic virus (CMV) and tomato aspermy virus (TAV). A recent study showed that NtCaM could mediate degradation of the dsRNA binding VSR 2b via the autophagy-like protein degradation pathway [27]. Indeed, either treatment with an autophagy inhibitor 3-MA or silencing of Beclin1/ATG6 impaired the degradation of CMV 2b protein [27]. These data suggest that autophagy could degrade VRS through plant rgs-CaM, although 3-MA has multiple off-target effects [28] and Beclin1/ATG6 also functions in vacuolar protein sorting, endosome-toGolgi retrograde transport or other pathways besides autophagy [29]. In addition, the in vitro application of an autophagy inhibitor wortmannin partially inhibit proteolysis of Tomato yellow leaf curl virus (TYLCV) proteins [30,31]. Further, autophagy genes are transcriptionally up-regulated by infection of some viruses in plants [32,33]. Recently, several studies provide clear evidences to prove that autophagy acts as an antiviral defense role against both DNA and RNA viruses in plants by targeting viral components for degradation [34–38]. Cotton leaf curl Multan virus (CLCuMuV) is a circular single-stranded DNA virus and associates with the disease-specific satellite DNA − Cotton leaf curl Multan betasatellite (CLCuMuB). CLCuMuB only encodes a single protein βC1, which is required for induction of disease symptoms and viral accumulation in plants [34]. Haxim et al. (2017) reported that autophagic machinery targeted and degraded viral βC1 through its interaction with the key autophagy protein ATG8 [34], which is conjugated with phosphatidylethanolamine (PE) and required for the autophagosome maturation in the autophagy pathway [39]. We found that βC1, but not its mutant βC1V32A, directly interacts with ATG8f. CLCuMuV infection activates autophagy and enhances the autophagic flux. Interestingly, disruption of autophagy by silencing of two ATG genes (ATG5 and ATG7) caused more severe leaf curl symptoms caused by CLCuMuV infection, increased the accumulation of viral DNA and βC1 protein whilst the enhanced autophagy by silencing of GAPC [20] impaired CLCuMuV infection. Furthermore, the mutant CLCuMuV carrying βC1V32A showed increased symptoms and viral DNA accumulation in plants [34]. In addition, autophagy is shown to have an antiviral defense against two additional geminiviruses including TYLCV and Tomato yellow leaf curl China virus (TYLCCNV) [34]. These data indicate that autophagy plays an antiviral role during geminiviral infection [34]. Cauliflower mosaic virus (CaMV) is a double-stranded DNA pararetrovirus [40]. Hafrén and colleagues (2017) showed that autophagy limited CaMV infection during its compatible interaction with Arabidopsis [38]. Severer symptoms were observed in the autophagy-deficient Arabidopsis mutants (atg5 and atg7) after the CaMV infection. Strikingly, the major structure protein P4 of CaMV capsid was specifically accumulated in the atg5 and atg7 mutant plants whilst other viral proteins did not show obvious difference [38]. Further, NBR1-mediated selective autophagy suppressed the accumulation of CaMV P4 and viral DNA at the cellular level [38]. These results suggest that autophagy targets viral capsid protein P4 and P4-assembled viral particles to mediate their degradation and restrict CaMV infection by NBR1-dependent manner [38]. Autophagy functions as an antiviral mechanism against not only plant DNA viruses but also plant RNA viruses. Turnip mosaic virus (TuMV) and Barley stripe mosaic virus (BSMV) are two plant positive single-stranded RNA viruses. Two reports showed that autophagy was induced by TuMV infection and restrict viral RNA accumulation [36,37]. Hafrén and colleagues (2018) found that the autophagy cargo receptor NBR1-dependent selective autophagy repressed viral accumulation by targeting the helper-component proteinase (HCpro), a viral suppressor of RNA silencing (VSR) [37]. Li et al. (2018) found that
During the incompatible plant-pathogen interactions, plant immunity is often associated with the hypersensitive response, a form of programmed cell death (HR PCD) at pathogen infection sites. Liu et al. (2005) first links plant immunity and PCD to autophagy [18]. Plant autophagy is induced by N-mediated resistance against tobacco mosaic virus (TMV) and this induction is dependent on host Beclin1 (an ortholog of the yeast and mammalian autophagy ATG6/VPS30). Meanwhile, we found that several ATG genes including Beclin1, PI3K/VPS43, ATG3, and ATG7 are required for limiting N-mediated HR PCD into TMV infection sites [18]. In addition, we also found that Beclin1 is required to limit HR PCD induced by another two resistance (R) genes (bacterial R gene Pto and fungal R gene Cf9) and two general pathogen elicitors (INF1 from Phytophthora infestans and P. syrinagae pv. DC3000). These findings suggest that autophagy negatively regulates plant immunity-related cell death in the tissues beyond pathogen infection sites [18]. The effect of autophagy on HR PCD at pathogen infection sites seems to be different from that on PCD beyond pathogen infection areas. Hofius et al. (2009) discovered that autophagy could contribute to HR PCD in a pro-death way. In Arabidopsis, atg knockout mutants atg7 and atg9 showed a delayed HR PCD induced by Pst DC3000 (avrRPS4) infection [19]. In addition, Han et al. (2015) reported that cytoplasmic glyceraldehyde-3-phosphat dehydrogenases (GAPCs) interacts with ATG3 directly and negatively regulates autophagy. Silencing of GAPCs enhanced N-mediated local plant resistance against TMV and HR cell death [20]. Furthermore, Xu et al. (2017) found that plant Bax inhibitor-1 (BI-1) interacted with the core autophagy-related protein ATG6/Beclin1 and positively regulated autophagy [21]. Silencing of BI-1 compromised autophagy induced by N-mediated resistance to TMV and enhanced Nmediated HR PCD. On the contrary, overexpression of BI-1 increased autophagic activity and enhanced defense to viral infection. Interestingly, the overexpressed BI-1 also caused autophagy-independent cell death in a dose-dependent manner, which suggest that autophagy plays both pro-survival and pro-death roles in nature [21]. Both PCD and ROS are involved in plant defense against virus infection [22–25]. Recently, it was reported that ROS level and PCD progress were both regulated by autophagy during the compatible plant-virus interaction. TMV local-infection on tomato leaves not only caused the PCD in the distal root tissues but also induced autophagy in root-tip cells [26]. The intracellular ROS induced by TMV infection wasexcreted into the cell wall and intercellular layer, which is accompanied with the enhanced expression of several ATG genes (ATG8, ATG5, ATG7, and ATG10). Interestingly, treatment with autophagy inhibitor 3-methyladenine (3-MA) caused an elevated systemic PCD process in the root-tip cells but did not affect the ROS level in the apical tissue, suggesting that ROS, as a signaling molecule, can trigger autophagy to eliminate the excessive intracellular ROS oxidative damage and maintain cell survival to limit viral infection [26]. 3. Autophagy functions as an antiviral mechanism against plant viruses Autophagy has been analyzed in mammals as a recognized player during host immune response for defensing diverse pathogens, such as viruses. First report of the effect of autophagy on plant defense against virus is derived from the study on N-mediated TMV resistance [18]. Silencing of several ATG genes (Beclin1, PI3K/VPS43, ATG3, and ATG7) enhanced TMV accumulation in the inoculated leaves but did not cause TMV spreading into systemic leaves in N-containing Nicotiana. benthamiana plants, suggesting that autophagy plays a role in local antiviral defense against TMV in N-mediated resistance against TMV. Recently, autophagy is found to play an important role in the 2
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Fig. 1. Role of autophagy during plant-virus interactions. Upper part indicates antiviral aspects of plant autophagy while autophagy manipulated by plant viral proteins shown in the bottom part. The names of virus families are illustrated in the interaction area respectively. (Upper panel) The viral suppressor of RNA silencing (VSR) protein 2b could undergo autophagic clearance by binding to rgsCaM. The VSR protein βC1 of geminivirus is degraded by autophagy by binding to ATG8. The capsid protein of caulimoviruses, P4, is a bona fide cargo of plant NBR1, thus cleared by selective autophagy. The GDD conserved motif-containing RdRps (NIb) is degraded through autophagy by binding with ATG6/Beclin1, a potential selective autophagy cargo receptor. (Lower panel) Evidence also exists that viruses can manipulates the autophagy to facilitate infection. RSV NSvc4 protein interferes with S-acylation of remorin and further induced its autophagic degradation to overcome remorin-mediated inhibition of virus movement. Viral P0 hijacks the SKP1-CUL-SCF ubiquitin-protein ligase to promote the degradation of AGO1. TuMV VPg protein interacts with SGS3 and could induce partial degradation of SGS3 by autophagy. VSR protein γb interact with the autophagy key factor ATG7 to disrupt the ATG7-ATG8 interaction to block autophagy, thus facilitates virus infection. CaMV P6 protein interrupts the interaction of NBR1 and P4 by inhibiting autophagy through some unknown way. VPg and 6k2 are found to block autophagy by the unknown way to accumulate the protein level of HCPro.
synthesis for virus-derived small interfering RNA (vsiRNA) production [50]. Viral genome-linked protein (VPg) encoded by TuMV interacted with SGS3 and induced the degradation of both SGS3 and its intimate partner RNA-dependent RNA polymerase 6 (RDR6). They discovered that VPg mediated degradation of SGS3 occurs via both the autophagy and 26S ubiquitin-proteasome pathways [51]. Harfen et al. (2017) proposed a model for the roles of autophagy in the CaMV infection cycle [38]. As autophagy cargo receptor, NBR1 targets viral capsid protein P4 and P4-assembled viral particles to mediate their degradation by autophagy, restricting CaMV infection. In contrast, CaMV P6 protein could disrupt the interaction between viral P4 and host NBR1 to protect viral replication factory inclusions from autophagic degradation [38]. In addition, virus-triggered autophagy also prevents extensive senescence and tissue death of infected plants in a largely NBR1-independent manner to facilitate viral particle acquisition by aphid vectors and CaMV transmission [38]. TuMV VPg and 6K2 proteins were found to antagonize antiviral capacity of NBR1-dependent autophagy by blocking NBR1 and HCpro degradation [37]. NBR1 accumulation might be affected by other viral proteins, indicating that other viral components might manipulate autophagy by some way. NBR1-independent bulk autophagy prevents premature plant death, thus promotes plant fitness to the benefit of virus production and potyvirus epidemiology [37]. Some viruses or viral factors also aff ;ect starch accumulation. For examples, TMV movement protein and BSMV γb protein induce starch accumulation [35,52]. Autophagy is reported to contribute to leaf starch degradation [53]. These viruses may inhibit autophagy to promote viral infection. Indeed, BSMV γb interferes with the interaction of ATG7 with ATG8 in a competitive manner to suppress autophagy for promoting viral infection [35]. NSvc4 protein of Rice stripe virus (RSV) is reported to interfere with S-acylation of Remorin and induced its autophagic degradation to overcome remorin-mediated inhibition of virus movement, thus facilitating virus infection [54] Li et al (2017) showed that the calmodulin-like protein rgs-CaM suppresses RNA silencing and promotes the infection of TYLCCNV by mediating degradation of SGS3 via autophagy [55]. In this study, silencing of NbBeclin1, NbPI3K, or NbVPS15 blocked the degradation of
Beclin1/ATG6, a core autophagy component, inhibited TuMV infection by its interaction to suppress and degrade viral RNA-dependent RNA polymerase (RdRp) [36]. TuMV NIb was targeted for Beclin1-mediated autophagic degradation likely through its interaction with Beclin1 and the autophagy adaptor protein ATG8a. Blocking autophagy by silencing either Beclin1 or ATG8a enhances NIb accumulation and promotes viral infection and vice versa. The interaction of Beclin1 with viral RdRp seems to be conserved, and extends to several RNA viruses including Cucumber green mottle mosaic virus and Pepino mosaic virus [36]. Thus, Beclin1 limits viral infection through suppression and also likely autophagic degradation of the viral RdRp. Yang et al. (2018) reported that autophagy also plays an antiviral defense against BSMV. Viral RNAs and proteins increased in ATG7- or ATG5-silenced plants compared with control plants [34–38] (Fig. 1, upper panel). 4. Autophagy is manipulated by plant viruses Apart from its antiviral defense, autophagy can also enhance the replication of some viruses in mammals [41–45]. Many viruses have evolved to escape or antagonize host autophagy in order to promote viral infection [15,46]. Viruses also exploit autophagy mechanisms for their own benefits [41–45]. In the course of plant-virus interactions, plants have evolved ingenious counter-attack mechanisms to diminish or eliminate invading viral pathogens. RNA silencing is a natural antiviral defense mechanism. For the effective infection, plant viruses encode VSRs to counteract host RNA silencing. Recent studies revealed that the VSR protein P0 from polerovirus triggered the degradation of ARGONAUTE1 (AGO1), a key component of RNA-induced silencing complex [47–49]. Viral P0, an F-box protein, hijacks the host S-phase kinase-associated protein1 (SKP1)-cullin1 (CUL1)-F-box protein (SCF) ubiquitin-protein ligase (E3) to promote ubiquitylation of AGO1. Interestingly, autophagy inhibitor treatment blocked AGO1 degradation. Further, AGO1 colocalized with ATG8a in the autophagic bodies [50]. These studies suggest that P0 triggers AGO1 degradation by the autophagy pathway. Cheng and his colleagues (2017) reported that TuMV infection reduced protein level of suppressor of gene silencing 3 (SGS3), a key component of the RNA silencing pathway that functions in double-stranded RNA 3
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5. Conclusions and perspectives Autophagy has emerged as a central part of plant defense against pathogens. This review highlights the importance of autophagy in plant-virus interactions. Although most papers have reported that autophagy acts as a positive regulator of defense against a wide range of plant pathogens [18,56,57], autophagy is also reported to promote pathogen invasion [54]. During the incompatible plant-virus interactions, autophagy prevents cells from death beyond viral infection sites. During the compatible plant-virus interactions, autophagy acts as an antiviral mechanism and mediates the degradation of viral components or particles, while plant viruses have evolved mechanisms to counteract or hijack autophagic processes to promote viral infection or virulence. In addition, autophagy may prevent senescence and tissue death of infected plants to promote plant fitness to the benefit of virus production and transmission [34]. Little is known about the mechanisms and the critical and perplexing role of autophagy in plant antiviral defense responses. Several viruses have been identified to modulate plant autophagy and viral infection can induce or block autophagy, depending on different plantvirus interactions. So far, it is still unclear what viral factor(s) is/are responsible for autophagy induction and which mechanisms pathways are involved in autophagy induction during plant-virus interactions. It is known that BSMV γb suppress autophagy by interacting with ATG7 to impair the interaction between ATG7 with ATG8 [35]. However, it is obscure how autophagy is suppressed during other plant-virus interactions. Selective autophagy cargo receptor NBR1/Joak2 is involved in plant antiviral defense against CaMV and TuMV [37]. Beclin1 is also thought as a selective autophagy cargo receptor to limit TuMV infection [36]. It is possible that more selective autophagy cargo receptors take part in plant antiviral immunity. Uncovering the molecular mechanism and role of autophagy in plant-virus interactions will help us to understand plant responses to viral infection. Manipulation of autophagy could provide the enhanced resistance to plant viruses. For example, silencing of GAPCs in transgenic plants will lead to increased defense against geminiviruses. Acknowledgements This work was supported by Ministry of Science and Technology of the People’s Republic of China (2017YFA0503401) and the National Natural Science Foundation of China (31530059 and 31421001). References [1] M. Incarbone, P. Dunoyer, RNA silencing and its suppression: novel insights from in planta analyses, Trends Plant Sci. 18 (7) (2013) 382–392. [2] K.K. Mandadi, K.G. Scholthof, Plant immune responses against viruses: how does a virus cause disease? Plant Cell 25 (5) (2013) 1489–1505. [3] S. Han, B. Yu, Y. Wang, Y. Liu, Role of plant autophagy in stress response, Protein Cell 2 (2011) 784–791. [4] D.J. Klionsky, P. Codogno, The mechanism and physiological function of macroautophagy, J. Innate Immun. 5 (5) (2013) 427–433. [5] D.J. Klionsky, The molecular machinery of autophagy: unanswered questions, J. Cell. Sci. 118 (Pt 1) (2005) 7–18. [6] A. Massey, R. Kiffin, A.M. Cuervo, Pathophysiology of chaperone-mediated autophagy, Int. J. Biochem. Cell Biol. 36 (12) (2004) 2420–2434. [7] N. Mizushima, B. Levine, A.M. Cuervo, D.J. Klionsky, Autophagy fights disease through cellular self-digestion, Nature 451 (7182) (2008) 1069–1075. [8] Y. Ohsumi, Molecular dissection of autophagy: two ubiquitin-like systems, Nat. Rev.
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