Activation of the unfolded protein response and autophagy after hepatitis C virus infection suppresses innate antiviral immunity in vitro
Activation of the unfolded protein response and autophagy after hepatitis C virus infection suppresses innate antiviral immunity in vitro
复制标题
DOI：
10.1172/jci41474
复制
发表时间：
2011-01-01
影响因子：
15.9
通讯作者：
Chen, Steve S-L
中科院分区：
文献类型：
--
作者：
Ke, Po-Yuan;Chen, Steve S-L
自噬是一种分解代谢细胞质成分的过程，它参与了RNA病毒与宿主之间相互作用的调节。然而，自噬在病毒生命周期中的功能作用机制仍然不清楚。丙型肝炎病毒（HCV）是一种单链、正义、可引起慢性肝病的膜包膜RNA病毒在此我们报道HCV诱导未折叠蛋白反应（UPR），进而激活自噬途径以促进人肝癌细胞中HCV RNA的复制进一步的分析表明，整个自噬过程直到完成自体溶酶体成熟都是促进HCV RNA复制所必需的，并且它通过抑制先天性抗病毒免疫来做到这一点。自噬途径分别激活或抑制由HCV衍生的病原体相关分子模式（PAMP）介导的IFN-β激活。用来自登革病毒（DEV）的PAMP获得了类似的结果，表明HCV和DEV都可以利用UPR-自噬途径来逃避先天免疫应答。总之，这些结果不仅定义了HCV诱导的自噬的生理意义，同时也揭示了HCV感染后宿主细胞反应的知识，以及探索控制HCV感染的治疗靶点
Autophagy, a process for catabolizing cytoplasmic components, has been implicated in the modulation of interactions between RNA viruses and their host However, the mechanism underlying the functional role of autophagy in the viral life cycle still remains unclear Hepatitis C virus (HCV) is a single-stranded, positive-sense, membrane-enveloped RNA virus that can cause chronic liver disease Here we report that HCV induces the unfolded protein response (UPR), which in turn activates the autophagic pathway to promote HCV RNA replication in human hepatoma cells Further analysis revealed that the entire autophagic process through to complete auto lysosome maturation was required to promote HCV RNA replication and that it did so by suppressing innate antiviral immunity Gene silencing or activation of the UPR-autophagy pathway activated or repressed, respectively, IFN-beta activation mediated by an HCV-derived pathogen-associated molecular pattern (PAMP) Similar results were achieved with a PAMP derived from Dengue virus (DEV), indicating that HCV and DEV may both exploit the UPR-autophagy pathway to escape the innate immune response Taken together, these results not only define the physiological significance of HCV-induced autophagy, but also shed light on the knowledge of host cellular responses upon HCV infection as well as on exploration of therapeutic targets for controlling HCV infection