How autophagy machinery is used by viruses for their replication.

病毒如何利用自噬机制进行复制。

• 批准号: RGPIN-2019-06932
• 负责人: Labonté, Patrick
• 金额: $ 2.33万
• 依托单位: Institut national de la recherche scientifique
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=716426
• 关键词: How; autophagy; machinery; used; viruses

Autophagy is a highly evolutionarily conserved process present in all eukaryotic cells. It involves the sequestration of regions of cytosol within double-membrane vesicles and delivery of the contents to lysosomes for degradation and recycling of the material. Recent advances on autophagy has demonstrated that it also plays an important role in antiviral host defence. However, despite its antiviral properties, several viruses have evolved to exploit autophagy or autophagy-related proteins to promote their own replication. To persist within the cell, many of the viruses that benefit from autophagy have developed strategies to successfully escape its antiviral activity. Importantly, the mechanisms used by viruses to subvert autophagy seem to be extremely diversified. A better comprehension of the strategies utilized by viruses to subvert autophagy will provide information on the co-evolution of both, virus and autophagy. Previously, we and others have clearly demonstrated that autophagy is strongly activated upon infection with several very divergent viruses including hepatitis B and C virus (HBV, HCV), morbillivirus and Zika virus. Indeed for these viruses, activation of autophagy favours viral replication while depletion of autophagy proteins impairs viral replication. Therefore, using HCV as a model, we propose to carry on our ongoing research on autophagy with the following aim: Identification of the strategies used by viruses to manipulate the autophagy machinery for their benefit. Objectives: i) Define the function of LC3B and its homologs in the membranous web formation and viral replication in HCV-infected cells. ii) Define how the autophagy machinery contributes to the formation of HCV replication site. Recently, we demonstrate that the proviral effect of autophagy on HCV replication was due to the direct involvement of the autophagy elongation complex (ATG5-12/16) in the formation of the HCV-induced membranous web that harbour the replication complex (RC). Strikingly, the presence of ATG5-12/16 at RC does not trigger LC3B accumulation at this site nor the degradation of viral structures. Since there is six LC3 homologs in mammalian cells, the participation of these homologs in HCV-induced membranous web formation and HCV replication will be characterized. Until now, our results demonstrated that HCV does not require the autophagy process but instead hijacks the autophagy machinery for the proper formation of its replication sites. How HCV avoid the degradative process of autophagy and how the autophagy machinery help HCV replication site formation will be studied. Many very divergent viruses have evolved to subvert autophagy for their own benefit. Using an evolutionary process, they managed to turn a genuinely antimicrobial process into a proviral process. Using HCV as a model of an enveloped positive-stranded RNA virus, we will decipher the host-virus interplay that coordinates the autophagy process in infected cells.

自噬是存在于所有真核细胞中的高度进化保守过程。它包括在双膜囊泡内隔离细胞质区域，并将内容物运送到溶酶体中进行降解和物质的再循环。自噬的最新进展表明，它在抗病毒宿主防御中也起着重要作用。然而，尽管它具有抗病毒特性，一些病毒已经进化到利用自噬或自噬相关蛋白来促进自身复制。为了在细胞内持续存在，许多受益于自噬的病毒已经发展出成功逃避其抗病毒活性的策略。重要的是，病毒用来破坏自噬的机制似乎是非常多样化的。更好地理解病毒用来破坏自噬的策略将为病毒和自噬的共同进化提供信息。