How autophagy machinery is used by viruses for their replication.

自噬是一个进化上高度保守的过程，存在于所有真核细胞中。它包括隔离双层膜小泡内的胞质溶胶区，并将内容物输送到溶酶体，以降解和回收材料。自噬的最新进展表明，它在抗病毒宿主防御中也发挥着重要作用。然而，尽管有抗病毒的特性，一些病毒已经进化到利用自噬或自噬相关蛋白来促进自己的复制。为了在细胞内持续存在，许多从自噬中受益的病毒已经制定了策略，成功地逃避了它的抗病毒活性。重要的是，病毒用来破坏自噬的机制似乎极其多样化。更好地理解病毒用来颠覆自噬的策略，将为病毒和自噬的共同进化提供信息。此前，我们和其他人已经清楚地证明，自噬在感染几种非常不同的病毒时被强烈激活，这些病毒包括乙肝病毒和丙型肝炎病毒(乙肝病毒、丙型肝炎病毒)、麻疹病毒和寨卡病毒。事实上，对于这些病毒来说，自噬的激活有利于病毒的复制，而自噬蛋白的耗尽则会削弱病毒的复制。因此，以丙型肝炎病毒为模型，我们建议继续我们正在进行的关于自噬的研究，目的如下：识别病毒操纵自噬机制以使其受益的策略。目的：1)明确LC3B及其同系物在丙型肝炎病毒感染细胞膜网络形成和病毒复制中的作用。Ii)确定自噬机制如何促进丙型肝炎病毒复制位点的形成。最近，我们证明了自噬对丙型肝炎病毒复制的前病毒效应是由于自噬延伸复合体(ATG5-12/16)直接参与了丙型肝炎病毒诱导的含有复制复合体(RC)的膜网的形成。值得注意的是，ATG5-12/16在RC的存在不会引发LC3B在该位置的积累，也不会导致病毒结构的降解。由于哺乳动物细胞中有六个LC3同源物，这些同源物在丙型肝炎病毒诱导的膜网形成和丙型肝炎病毒复制中的参与将被表征。到目前为止，我们的结果表明，丙型肝炎病毒不需要自噬过程，而是劫持了自噬机制，以正确地形成其复制位点。丙型肝炎病毒如何避免自噬的降解过程，以及自噬机制如何帮助丙型肝炎病毒复制位点的形成将被研究。许多非常不同的病毒已经进化到为了自己的利益而颠覆自噬。通过一个进化过程，他们成功地将一个真正的抗菌过程转变为前病毒过程。利用丙型肝炎病毒作为包膜正链RNA病毒的模型，我们将破译宿主与病毒之间的相互作用，从而协调受感染细胞的自噬过程。

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.