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Botanical Research
Vol. 11  No. 03 ( 2022 ), Article ID: 51718 , 11 pages
10.12677/BR.2022.113039

自噬在植物抵御病毒侵染中的作用

周涛

浙江师范大学，浙江 金华

收稿日期：2022年4月17日；录用日期：2022年5月17日；发布日期：2022年5月26日

摘要

细胞自噬是真核生物中一种非常保守的再循环系统，通过降解和循环再利用细胞成分，维持细胞内稳态以及进应对细胞应激。近些年的研究表明细胞自噬不仅维持细胞内稳态，并在调节免疫相关细胞死亡、抗病毒以及促进病毒致病方面发挥着重要作用。在这里，我们综述了细胞自噬的分子机理，以及在植物抵抗病毒侵染中的相互作用，旨在为自噬相关研究提供参考。

关键词

细胞自噬，细胞死亡，分子机理，免疫防御反应

Role of Autophagy in Plant Resistance to Virus Infection

Tao Zhou

Zhejiang Normal University, Jinhua Zhejiang

Received: Apr. 17th, 2022; accepted: May 17th, 2022; published: May 26th, 2022

ABSTRACT

Autophagy is a very conservative recycling system in eukaryotes. It maintains intracellular homeostasis and responds to cell stress by degrading and recycling cellular components. Recent studies have shown that autophagy not only maintains intracellular homeostasis, but also plays an important role in regulating immune related cell death, and antiviral and promoting virus pathogenesis. Here, we review the molecular mechanism of autophagy and its interaction with plant resistance to virus infection, in order to provide a reference for autophagy related research.

Keywords:Autophagy, Cell Death, Molecular Mechanism, Immune Defense Response

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

自噬是真核生物中保守的机制，对于细胞器的更新以及物质重复利用具有重要意义。自噬可按其进入溶酶体的途径不同分为三种：分子伴侣转导的自噬(CMA)、微自噬和巨自噬 [1] [2] [3]。微自噬和CMA都不需要自噬体的参与，而是依赖于溶酶体/液泡的降解功能。巨自噬，通常简称为自噬，是一种高度保守的过程，自噬体双层膜结构会包裹细胞器以及大分子物质，通过膜融合的形式进入溶酶体或者液泡中形成自噬小体，自噬小体在溶酶体或者液泡破裂释放出内容物进行降解或者细胞器的更新 [4]。在CMA中，单个细胞溶质蛋白被一种伴侣蛋白识别，该蛋白将其送到溶酶体进行降解。到目前为止，这一过程仅在哺乳动物中发现 [5]。在微自噬过程中，细胞质物质与液泡表面结合，被内陷的液泡膜吞没，然后断裂形成自噬体。在此过程中，一部分细胞组分会被阻隔在一种叫做“自噬”的双层结合物中，称为细胞质中的自噬体。成熟的自噬体被输送到液泡进行降解。在自噬的类型中，巨自噬是最具特征的。此外，自噬也可以根据货物特异性分为非选择性批量自噬和选择性自噬 [4] [6]。在非选择性批量自噬过程中，细胞成分被不加区分地吞噬在自噬体中并降解。选择性自噬包括将特定的蛋白质或细胞器吞噬到由受体介导的自噬体中。在正常生长条件下，自噬有助于细胞维持代谢物稳态，而在应激条件下，自噬被激活降解受损的细胞器或蛋白质聚集物以进行营养循环 [7] [8] [9] [10]。自噬还参与了程序性细胞死亡(PCD)的调节，其功能障碍与各种病理条件和疾病有关 [11] [12]。起初，自噬被认为是一种营养循环和能量的非特异性(“散装”)过程，现在很多研究表明，自噬通过高选择性机制消除多余、有害或受损的细胞质成分，从单个蛋白质到整个细胞器 [13] [14]。自噬的中心过程是由一组自噬相关基因(ATGs)完成的，这些基因最初在酵母 [10] 中被鉴定和研究。在酵母中已经发现了约有40个ATG基因，其中大部分在植物 [10] [15] 中有同源性，这表明核心ATG过程在进化过程中是保守的。

2. 自噬的分子机制

自噬作为第三种途径，其特征是重新形成一个双标记膜吞噬的囊泡，即自噬小体，然后与晚期核内体或溶酶体融合以降解其货物。这些膜源包括粗面内质网 [16] [17]、高尔基体 [18] [19]、外核膜 [20]、外线粒体膜 [21] [22] 和质膜 [23]。自噬体的形成和降解需要30多种基因产物，即自噬相关(ATG)蛋白。这些“核心”ATG蛋白由五个功能组组成：1) ATG1/ULK蛋白激酶复合物 [24]，2) ATG9-ATG2-ATG18复合物 [25] [26] [27]，3) 自噬特异性磷脂酰肌醇3-激酶(PI3K)复合物 [28]，4) ATG12-ATG5-ATG16/ATG12- ATG5-ATG16L1复合物 [29] [30]，5) ATG8家族蛋白质脂质系统 [31] [32]。这些“核心”ATG蛋白共同完成自噬体的形成(图1)。

2.1. 自噬启动

自噬启动的标志物是自噬体的形成，其启动过程主要依赖于ATG1/ULK复合物 [33]。ULK1蛋白激酶复合物由ULK1 (一种蛋白激酶)、ATG13、FIP200和ATG1组成 [24] [34] [35] [36] [37] [38]。mTOR激酶直接磷酸化ATG13，负调节自噬 [36]。ATG1对ATG13和ULK1的稳定性和基础磷酸化很重要 [34] [35]。FIP200对ULK1 [38] 的稳定性和磷酸化非常重要。ULK1蛋白激酶经过磷酸化 [39] 和泛素化 [40] [41] 等修饰后，对自噬体的形成至关重要。ULK1激酶活性受mTORC1和AMPK调节 [42]。

Figure 1. Schematic diagram of plant macroautophagy [43]

图1. 植物巨自噬的示意图 [43]

ATG9-ATG2-ATG18复合物由ATG9 = mATG9、ATG2和ATG18 = WIPI-1组成。ATG9是酵母中唯一完整的ATG膜蛋白 [44] [45]；哺乳动物中同源物mATG9 = ATG9L1以及ATG9L2广泛表达，后者特异于胎盘和垂体 [27]。在营养丰富的条件下，mATG9定位于跨高尔基体网络和部分内体，而在饥饿条件下，mATG9定位于自噬体，其过程依赖于ULK1 [27]。在自噬过程中，mATG9和磷脂酰肌醇3-磷酸(P3I)结合蛋白WIPI-1 = ATG18定位于LC3阳性斑点，使LC3-II = ATG8-PE成为一个有希望的自噬体标记物 [25] [46]。ATG18在酵母中与ATG2组成性相互作用，ATG9在饥饿条件下与ATG2-ATG18复合物相互作用 [47]。ATG27是酵母中ATG9的自噬依赖循环所必需的 [48]。

自噬体产生的部位以膜中的磷脂酰肌醇3-磷酸(PI3)为标志，该膜由III型PI3激酶复合物沉积在膜上，其核心复合物含有PI3激酶VPS34、VPS15、ATG14L和ATG6/Beclin-1 [49]。在酵母中，ATG14-Vps34- Vps15-ATG6复合体在细胞内具有重要的功能，而Vps38-Vps34-Vps15-ATG6复合物对液泡蛋白分选至关重要 [50]。

2.2. 自噬体的形成与降解

自噬启动以后，自噬体膜需要通过两个泛素样系统实现自噬体膜的延伸 [49]。ATG12–ATG5/ATG16L1是第一个泛素样系统，对隔离膜的形成和延伸至关重要 [51]。虽然ATG12和泛素的氨基酸序列不同，但ATG12确实具有泛素折叠 [30]。在ATG12偶联体系中，ATG12被一种类似e1的酶ATG7激活；转移到E2样酶ATG10，并与ATG5结合形成ATG12-ATG5偶联物 [29] [30] [52] [53] [54]。ATG12是一个具有结构性泛素折叠的修饰物，ATG16与ATG12-ATG5偶联物相互作用，形成一个多聚复合物 [55] [56] [57]。在许多组织和细胞系中，大多数内源性的ATG5和ATG12作为ATG12-ATG5偶联物存在，在自噬过程中观察到ATG12-ATG5偶联物的数量几乎没有增加。

LC3偶联是第二个泛素样系统，泛素样蛋白ATG8/LC3和磷脂酰乙醇胺(PE)在C端结合生成ATG8-PE。这一过程是由E1-E2-E3共同催化的，其中E1样酶ATG7引导ATG8转移到E2样酶ATG3上，形成由硫酯键连接的ATG3-ATG8中间体。然后，ATG12-ATG5-ATG16复合物作为E3酶促进ATG8从ATG3转移到PE脂质。在自噬小体形成过程中，ATG8-PE被ATG4裂解，释放出脱脂的ATG8 (ATG8G116)和PE [33]。在自噬体膜上，它通过泛素和LC3结合蛋白p62、NBR1和NDP52 [58] [59] [60] 介导泛素化底物的募集，如蛋白质聚集体和细胞器，也可能是自噬体膜延长和囊泡折叠的膜融合 [61]。当ATG8/LC3留在内自噬体膜上时，ATG4将其从外自噬体膜上切割，并且ATG12–ATG5/ATG16L1在自噬体完成后被回收。成熟的自噬体随后与植物中的液泡融合(图2)，自噬体中的内容物在液泡中降解。

ATG12结合与LC3脂质化密切相关。ATG5缺乏会导致LC3脂质沉积缺陷 [51] [62]。哺乳动物中ATG3的缺失导致ATG12-ATG5结合物的减少以及LC3脂质化的损害 [63]，并与自噬体形成缺陷有关，包括隔离膜的长度缺陷和完全闭合，导致自噬体畸形。在细胞松弛的ATG3中，ATG16L和ATG5定位于伸长的二分解膜/不完全自噬体，表明在缺乏LC3脂质化的情况下，分离膜会伸长 [63]。

3. 自噬与植物病毒的相互作用

最初，巨自噬被描述为对饥饿的反应，循环细胞质成分以产生能量和细胞存活的大分子构建块。现在已经部分描述了响应氨基酸剥夺和生长因子退出导致巨自噬上调的信号 [64]。此外，最近人们认识到病原体检测还可以上调巨自噬作为先天免疫效应功能 [65]。病原体相关分子模式(PAMP)或病原体诱导的细胞器变化的识别会刺激巨自噬。尽管根据巨自噬在胞质细胞器和蛋白质聚集体清除中的作用可以直观地预测，胞质PAMP识别可能优先增强这一途径，但PAMP识别受体(PRR)识别细胞外和细胞内结构已被描述为上调巨自噬。目前，关于触发巨自噬的表面和内体受体，迄今为止主要评估了Toll样受体(TLR)的巨自噬调节作用 [66] [67] [68]。其中TLR4为细菌脂多糖受体(LPS)和单链RNA受体，TLR7在小鼠巨噬细胞RAW264.7中诱导强烈的自噬体积累 [66] [67] [69]。TLR4在LPS参与后招募接头分子MyD88和Trif，它们反过来结合泛素化的ATG6/Beclin-1以增强大自噬 [66] [70]，可能是通过启动细胞膜上的自噬体形成 [23]。因此，TLR信号似乎上调了小鼠吞噬细胞的巨自噬。除了TLR介导的上调外，胞质PRRs也被证明可以上调巨自噬 [71]。

3.1. 植物通过自噬清除感染病毒

在植物中，自噬最初与抗病毒过敏反应(HR)的限制和促进有关，这是一种局部细胞程序性死亡(programmed cell death, PCD)反应，通常由效应子触发免疫(ETI)期间核苷酸结合的富含亮氨酸重复序列(NLR)免疫受体激活而触发。Liu等人首次发现了在含有烟草花叶病毒(TMV)无毒株的NLR型N基因中沉默自噬相关基因ATG6/Beclin1会导致HR损伤中的病毒水平增加以及细胞死亡不受限制地扩散到未感染的组织中。此外，沉默其他自噬相关基因PI3K/VPS34，ATG3和ATG7也会导致了TMV感染时不受控制的HR-PCD [72]。自Liu等人首次发现了自噬在植物抗病毒免疫中的作用之后。越来越多的证据揭示了植物自噬的植物抗病毒免疫中的作用(图2) [73]。比如，ATG3介导的自噬增强通过细胞溶质3-磷酸甘油醛脱氢酶(GAPC)基因的下调刺激HR和对TMV的抗病性 [74]。植物Bax抑制剂-1 (BI-1)是一种高度保守的细胞死亡调节因子，它与ATG6/Beclin1相互作用，正向调节N介导的TMV抗性诱导的自噬。BI-1的沉默降低自噬活性并增强N介导的PCD。BI-1的过表达会激活自噬，并以剂量依赖性方式导致自噬依赖性细胞死亡。因此，植物BI-1可能在病原体感染期间以自噬依赖性方式发挥促生存和促死亡的作用 [75]。这些观察结果增加了自噬作为免疫相关PCD介质，同时抑制不同植物病理系统中的应激和疾病相关(坏死)细胞死亡的新兴观点 [76] [77] [78] [79]。

Figure 2. Antiviral and proviral effects of autophagy in plants [80]

图2. 自噬在植物中抗病毒作用和前病毒作用 [80]。

花椰菜花叶病毒(CaMV)是一种双链DNA副病毒，通过BRCA1 (NBR1)的货物受体邻居直接结合并介导病毒衣壳蛋白和颗粒的液泡清除，导致限制病毒感染 [81]。缺乏核心自噬机制(ATG5和ATG7)的拟南芥植株中CaMV症状的严重程度加剧，并观察到ATG5和ATG7突变体中的疾病症状比野生型和对照植株明显得多。受感染的ATG5和ATG7突变体植株的成熟叶片显示出早期衰老和组织坏死的迹象 [81]。进一步研究证明，NBR1依赖的过程可以限制萝卜花叶病毒(TuMV)对拟南芥的感染，TuMV是一种正链RNA马铃薯Y病毒 [82]。然而，选择性自噬并没有去除整个颗粒，而是将RNA沉默(VSR) HCpro的病毒抑制子与前病毒RNA颗粒联合作为靶点 [83]，这也表明颗粒吞噬是抗病毒反应的一部分 [82]。此外，烟草病毒属的黄瓜绿斑驳花叶病毒(CGMMV)和马铃薯花叶病毒属的佩皮诺花叶病毒(PepMV)，也有着相似的抗病毒机制。它们编码的RDRP也与Beclin1相互作用，沉默Beclin1会导致比对照植物更严重的症状。作为一种关键的自噬调节因子，Beclin1通过自噬途径限制RNA病毒感染，以抑制和降解病毒RDRP [84]。

棉叶卷曲木尔坦病毒(CLCuMuV)相关的βC1棉叶卷曲木尔坦β卫星(CLCuMuB)被募集到自噬体，随后通过与ATG8f直接相互作用在液泡中降解，βC1-ATG8f相互作用的破坏导致病毒DNA积累增加 [75]。此外，GAPC下调激活的自噬作用增强了底栖动物的抗病性。自噬的抑制作用也扩展到其他双子病毒，比如番茄黄叶卷曲病毒(TYLCV)和番茄黄叶卷曲中国病毒(TYLCCNV) [75]。

钙调素样蛋白rgs-CaM可能是一种选择性自噬受体，通过介导宿主因子或病毒蛋白的降解来防御病毒感染 [85] [86]。烟草rgs-CaM与多种VSR相互作用，包括来自马铃薯Y病毒的HCpro和来自黄瓜花叶病毒(CMV)和番茄不孕病毒的2b蛋白。通过rgs-CaM识别和降解导宿主因子或病毒蛋白，从而加强宿主对病毒感染防御 [87]。这些观察结果一致，rgs-CaM的过度表达导致植物对CMV感染不太敏感，而rgs-CaM表达的敲除增加了对CMV感染的易感性。因此，rsg-CaM可能是多个VSR的选择性自噬受体，积极参与抗病毒RNA干扰(RNAi)防御 [87]。最近，Jiang等人 [87] 发现了一种新的货运受体NbP3IP，其功能以前未知，它与水稻条纹病毒(RSV)的P3蛋白(VSR)和NbATG8f特异性相互作用。这些相互作用介导P3蛋白的选择性降解，并限制RSV感染。

3.2. 病毒操控自噬满足自身需要

在植物与病毒的相互作用过程中，许多病毒进化出操纵宿主自噬机制来满足自身的需要。植物病毒通过自噬途径降解防御相关蛋白，对植物产生不利影响，从而促进感染。马铃薯叶卷病毒属编码RSS P0，通过自噬途径触发关键RNA沉默成分ARGONAUTE1 (AGO1)的降解。由于AGO1在自噬结构中与ATG8a共定位，E64d或3-MA抑制治疗后，AGO1的降解被阻断。马铃薯叶卷病毒属诱导的降解或AGO1通过自噬途径抑制病毒抗性并促进植物中的病毒感染 [88]。同样，TuMV感染导致SGS3及其优先伙伴RNA依赖性RNA聚合酶6 (RDR6)降解。蛋白酶体抑制剂MG132或自噬抑制剂3-MA显著减弱病毒诱导的SGS3和RDR6降解，表明泛素蛋白酶体和自噬途径均参与重要RNA沉默成分的降解。TuMV编码的VPg直接与SGS3相互作用并触发SGS3和RDR6降解，从而减弱宿主RNA沉默并促进病毒感染。另外两种由马铃薯Y病毒编码的VPg，属于烟草蚀刻病毒(TEV)和大豆花叶病毒(SMV)，也与SGS3相互作用，表明SGS3和VPg之间的相互作用以及RNA沉默成分的降解是马铃薯Y病毒的一般机制 [89]。番茄黄叶中国病毒(TYLCCNV)编码的βC1β亚基上调了钙调蛋白样蛋白(CaM)的表达，后者与底栖动物体内的SGS3蛋白相互作用。CaM和SGS3的瞬时共表达诱导自噬体活性降解宿主细胞中的SGS3，而3-MA处理或沉默本塞姆氏烟草中的Beclin1、PI3K或VPS15可抑制SGS3降解。据报道，TYLCV可在病毒复制阶段激活白粉虱自噬，激活白粉虱自噬可导致病毒外壳蛋白和基因组DNA降解，抑制病毒传播。ATG3或ATG9的沉默增加了粉虱中的病毒载量，并促进了病毒传播，这表明粉虱自噬抑制了植物和昆虫中的病毒感染。 [90]。

3.3. 病毒抵御宿主自噬策略

植物通过自噬来防御病毒侵染，然病毒在长期的进化过程中，进化出了抵抗植物自噬的策略。CaMV编码的P4与NBR1相互作用，促进选择性自噬，以靶向P4和病毒颗粒对抗CaMV感染。另一方面，病毒编码的P6可以干扰P4和NBR1之间的相互作用，从而允许CaMV诱导的病毒包涵体和传播体对抗NBR1，从而阻止病毒蛋白质和颗粒的降解。该报告揭示了病毒通过自噬降解成功感染的潜在策略 [91]。虽然在BSMV感染过程中，病毒RNA在自噬缺陷的植物中积累，但Yang等人 [92] 发现BSMV感染可以抑制自噬。BSMV VSR γb足以抑制通过与ATG7 [92] 相互作用而产生的自噬。ATG7属于两个泛素样系统，ATG12-ATG5和ATG7-ATG3复合物 [93]。γb是一种来自大麦条纹花叶病毒(BSMV)的VSR，在感染宿主期间BSMV γb蛋白通过直接与ATG8竞争ATG7结合，导致ATG7和ATG8之间的关联受损来破坏自噬介导的抗病毒防御 [92]。与此相似，在马铃薯晚疫病菌分泌的RXLR (Arg-X-Leu-Arg)效应器PexRD54含有AIM，对ATG8CL的结合亲和力高于NBR1，通过与ATG8CL结合的NBR1竞争来抑制NBR1介导的自噬防御 [94]。此外，最新研究表明，与番茄黄叶卷曲中国病毒(TYLCCNV)相关的番茄黄叶卷曲中国β亚基(TYLCCNB)编码的βC1和NbNBR1 βC1之间的相互作用抑制了E3连接酶NbRFP1和βC1之间的相互作用，从而使βC1远离NbRFP1介导的降解 [95]。

4. 总结与展望

细胞自噬在调节植物的生长发育、维持细胞内稳态、调节免疫相关的细胞程序性死亡、抗病毒以及促进病毒致病方面发挥着至关重要的作用。因此，探究自噬在植物免疫防御反应中的分子机制以及功能有着非常重要的意义。虽然目前对于自噬在植物免疫防御反应中的分子机制以及功能已经取得了一些成果，且研究手段也日渐走向成熟，但相对自噬这个复杂的机制来说，可能只是冰山一角，许多自噬相关基因在植物免疫防御反应中的分子机制以及功能还有待发掘。

在未来，自噬在植物抗病毒以及促进病毒致病的分子机制和作用需要进一步深入的研究。

文章引用

周 涛. 自噬在植物抵御病毒侵染中的作用
Role of Autophagy in Plant Resistance to Virus Infection[J]. 植物学研究, 2022, 11(03): 329-339. https://doi.org/10.12677/BR.2022.113039

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