Autophagy protects against Sindbis virus infection of the central nervous system.
Autophagy protects against Sindbis virus infection of the central nervous system.
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DOI：
10.1016/j.chom.2010.01.007
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发表时间：
2010-02-18
影响因子：
30.3
通讯作者：
Levine B
中科院分区：
文献类型：
--
作者：
Orvedahl A;MacPherson S;Sumpter R Jr;Tallóczy Z;Zou Z;Levine B
自噬在抗病毒免疫中的作用。然而，目前还不清楚内源性自噬基因是否能保护脊椎动物免受病毒性疾病的侵害。使用三种不同的方法在病毒感染的神经元中表达自噬基因Atg5，我们发现Atg5功能的丧失增加了小鼠对致死性辛德毕斯病毒CNS感染的易感性。这种表型与病毒蛋白清除延迟、细胞p62衔接蛋白积累增加和神经元细胞死亡增加有关，但与CNS病毒复制水平改变无关。在体外，p62与辛德毕斯病毒衣壳蛋白相互作用，并且p62的基因敲低阻断病毒衣壳对自噬体的靶向。此外，p62或自噬基因敲除会增加病毒衣壳的积累并加速病毒诱导的细胞死亡，而不会影响病毒复制。这些结果表明自噬在哺乳动物抗病毒防御中的一种新功能：一种细胞自主机制，其中p62衔接子介导的自噬病毒蛋白清除促进细胞存活。
Autophagy functions in antiviral immunity. However, it is not yet known whether endogenous autophagy genes protect against viral disease in vertebrates. Using three different approaches to inactivate the autophagy gene Atg5 in virally-infected neurons, we found that loss of Atg5 function increases mouse susceptibility to lethal Sindbis virus CNS infection. This phenotype is associated with delayed clearance of viral proteins, increased accumulation of the cellular p62 adaptor protein, and increased cell death in neurons, but not with altered levels of CNS viral replication. In vitro, p62 interacts with Sindbis virus capsid protein and genetic knockdown of p62 blocks the targeting of viral capsid to autophagosomes. Moreover, p62 or autophagy gene knockdown increases viral capsid accumulation and accelerates virus-induced cell death without affecting virus replication. These results suggest a novel function for autophagy in mammalian antiviral defense: a cell-autonomous mechanism in which p62 adaptor-mediated autophagic viral protein clearance promotes cell survival.