Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
Cell Host Microbe. 2010 Feb 18;7(2):115-27. doi: 10.1016/j.chom.2010.01.007.
Autophagy functions in antiviral immunity. However, the ability of endogenous autophagy genes to protect against viral disease in vertebrates remains to be causally established. Here, we report that the autophagy gene Atg5 function is critical for protection against lethal Sindbis virus (SIN) infection of the mouse central nervous system. Inactivating Atg5 in SIN-infected neurons results in delayed clearance of viral proteins, increased accumulation of the cellular p62 adaptor protein, and increased cell death in neurons, but the levels of viral replication remain unaltered. In vitro, p62 interacts with SIN 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 function for autophagy in mammalian antiviral defense: a cell-autonomous mechanism in which p62 adaptor-mediated autophagic viral protein clearance promotes cell survival.
自噬在抗病毒免疫中发挥作用。然而，内源性自噬基因在脊椎动物中抵抗病毒病的能力仍有待因果关系的建立。在这里，我们报告自噬基因 Atg5 的功能对于保护小鼠中枢神经系统免受致命辛德毕斯病毒（SIN）感染至关重要。在 SIN 感染的神经元中失活 Atg5 会导致病毒蛋白的清除延迟，细胞 p62 衔接蛋白的积累增加，神经元死亡增加，但病毒复制水平保持不变。在体外，p62 与 SIN 衣壳蛋白相互作用，p62 的遗传敲低会阻止病毒衣壳靶向自噬体。此外，p62 或自噬基因敲低会增加病毒衣壳的积累并加速病毒诱导的细胞死亡，而不影响病毒复制。这些结果表明自噬在哺乳动物抗病毒防御中具有功能：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。
