VDAC1 balances mitophagy and apoptosis in leafhopper upon arbovirus infection
VDAC1 balances mitophagy and apoptosis in leafhopper upon arbovirus infection
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VDAC1平衡虫媒病毒感染后叶蝉的线粒体自噬和细胞凋亡
DOI：
10.1080/15548627.2022.2150001
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发表时间：
2022-12-01
期刊：
影响因子：
13.3
通讯作者：
Wei, Taiyun
中科院分区：
文献类型：
--
作者：
Chen, Qian;Jia, Dongsheng;Wei, Taiyun
摘要 线粒体自噬是自噬的一种形式，在病毒感染过程中选择性地去除受损的线粒体并减弱线粒体依赖性细胞凋亡，但虫媒病毒如何平衡线粒体自噬和细胞凋亡以促进昆虫媒介的持续病毒感染而不引起明显的健康成本仍然难以捉摸。在这里，我们鉴定了线粒体VDAC1（电压依赖性阴离子通道1），它可以被稻瘿矮病毒（RGDV）（一种植物无包膜双链RNA病毒）的非结构蛋白Pns11劫持，以协同激活叶蝉载体中的促病毒广泛线粒体自噬和有限细胞凋亡。 Pns11 与 VDAC1 构建的纤维结构的直接目标诱导线粒体变性。此外，退化的线粒体被招募到 Pns11 诱导的吞噬细胞中，通过 VDAC1 与 Pns11 和自噬蛋白 ATG8 的相互作用启动线粒体自噬。这种由 Pns11 和 VDAC1 介导的线粒体自噬需要经典的 PRKN/Parkin-PINK1 途径。 VDAC1通过控制凋亡信号分子通过其孔的释放来调节细胞凋亡，而抗凋亡蛋白GSN（凝溶胶蛋白）可以与VDAC1孔结合。我们证明，Pns11 与 VDAC1 和凝溶胶蛋白的相互作用降低了 VDAC1 表达，但增加了 GSN 表达，从而阻止了病毒感染区域的广泛凋亡反应。同时，病毒诱导的线粒体自噬也有效阻止了广泛的细胞凋亡反应，降低了细胞凋亡引起的昆虫健康成本。随后载有病毒的线粒体吞噬体与溶酶体的融合被阻止，因此此类线粒体吞噬体被用于病毒粒子在昆虫体内的持续传播。我们的结果揭示了虫媒病毒平衡和利用线粒体自噬和细胞凋亡的新策略，从而为昆虫载体中的病毒持续繁殖提供最佳的细胞内环境。缩写：ATG：自噬相关； BNIP3：BCL2 相互作用蛋白 3； CYCS/CytC：细胞色素c，体细胞； dsGSN：靶向 GSN/凝溶胶蛋白的双链 RNA； dsGFP：靶向绿色荧光蛋白的双链RNA； dsPRKN：靶向 PRKN 的双链 RNA； dsPns11：靶向Pns11的双链RNA； dsRNA：双链RNA； EC：上皮细胞； GST：谷胱甘肽S-转移酶； LAMP1：溶酶体相关膜蛋白1； Mito：线粒体； Mmg：中中肠； MP，线粒体吞噬体； PG，吞噬细胞。 padp：首次接触患病植物后； PINK1：PTEN 诱导激酶 1； RGDV：稻瘿矮化病毒； SQSTM1: 隔离体 1; TOMM20：线粒体外膜转位酶20； TUNEL：末端脱氧核苷酸转移酶 dUTP 缺口末端标记； VDAC1：电压依赖性阴离子通道 1。
ABSTRACT Mitophagy is a form of autophagy that selectively removes damaged mitochondria and attenuates mitochondrial-dependent apoptosis during viral infection, but how arboviruses balance mitophagy and apoptosis to facilitate persistent viral infection in insect vectors without causing evident fitness cost remains elusive. Here, we identified mitochondrial VDAC1 (voltage-dependent anion channel 1) that could be hijacked by nonstructural protein Pns11 of rice gall dwarf virus (RGDV), a plant nonenveloped double-stranded RNA virus, to synergistically activate pro-viral extensive mitophagy and limited apoptosis in leafhopper vectors. The direct target of fibrillar structures constructed by Pns11 with VDAC1 induced mitochondrial degeneration. Moreover, the degenerated mitochondria were recruited into Pns11-induced phagophores to initiate mitophagy via interaction of VDAC1 with Pns11 and an autophagy protein, ATG8. Such mitophagy mediated by Pns11 and VDAC1 required the classical PRKN/Parkin-PINK1 pathway. VDAC1 regulates apoptosis by controlling the release of apoptotic signaling molecules through its pore, while the anti-apoptotic protein GSN (gelsolin) could bind to VDAC1 pore. We demonstrated that the interaction of Pns11 with VDAC1 and gelsolin decreased VDAC1 expression but increased GSN expression, which prevented the extensive apoptotic response in virus-infected regions. Meanwhile, virus-induced mitophagy also effectively prevented extensive apoptotic response to decrease apoptosis-caused insect fitness cost. The subsequent fusion of virus-loaded mitophagosomes with lysosomes is prevented, and thus such mitophagosomes are exploited for persistent spread of virions within insect bodies. Our results reveal a new strategy for arboviruses to balance and exploit mitophagy and apoptosis, resulting in an optimal intracellular environment for persistent viral propagation in insect vectors. Abbreviations: ATG: autophagy related; BNIP3: BCL2 interacting protein 3; CYCS/CytC: cytochrome c, somatic; dsGSN: double-stranded RNAs targeting GSN/gelsolin; dsGFP: double-stranded RNAs targeting green fluorescent protein; dsPRKN: double-stranded RNAs targeting PRKN; dsPns11: double-stranded RNAs targeting Pns11; dsRNA: double-stranded RNA; EC: epithelia cell; GST: glutathione S-transferase; LAMP1: lysosomal associated membrane protein 1; Mito: mitochondrion; Mmg: middle midgut; MP, mitophagosome; PG, phagophore. padp: post-first access to diseased plants; PINK1: PTEN induced kinase 1; RGDV: rice gall dwarf virus; SQSTM1: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VDAC1: voltage dependent anion channel 1.