Flavivirus NS4A-induced Autophagy Protects Cells against Death and Enhances Virus Replication
Flavivirus NS4A-induced Autophagy Protects Cells against Death and Enhances Virus Replication
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DOI：
10.1074/jbc.m110.192500
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发表时间：
2011-06-24
影响因子：
4.8
通讯作者：
Zakeri, Zahra
中科院分区：
文献类型：
--
作者：
McLean, Jeffrey E.;Wudzinska, Aleksandra;Zakeri, Zahra
黄病毒包括最普遍和医学上最具挑战性的病毒。黄病毒对上皮细胞和肝细胞的持续性感染是常见的，这些细胞不经历细胞死亡。在这里，我们报告说，在上皮细胞中，上调自噬黄病毒感染后显着增强病毒复制和一个黄病毒基因，NS 4A，独特地决定了上调自噬。登革-2和莫多克（一种鼠黄病毒）杀死原代鼠巨噬细胞，但保护上皮细胞和成纤维细胞免受几种损伤引起的死亡。黄病毒诱导的保护源自自噬的上调，因为通过饥饿或雷帕霉素的哺乳动物靶标的失活而上调自噬也保护细胞免受损伤，而通过PI 3 K的失活而抑制自噬使黄病毒赋予的保护无效。自噬的抑制也限制了登革-2和莫多克病毒在上皮细胞中的复制。黄病毒NS 4A的表达足以诱导PI 3 K依赖性自噬并保护细胞免于死亡;其他病毒基因（包括NS 2A和NS 4 B）的表达不能保护细胞免受几种应激源的影响。黄病毒NS 4A蛋白在上皮细胞中诱导自噬，从而在感染期间保护它们免于死亡。由于自噬对黄病毒在这些细胞中的复制至关重要，因此NS 4A也被鉴定为黄病毒复制的关键决定因素。
Flaviviruses include the most prevalent and medically challenging viruses. Persistent infection with flaviviruses of epithelial cells and hepatocytes that do not undergo cell death is common. Here, we report that, in epithelial cells, up-regulation of autophagy following flavivirus infection markedly enhances virus replication and that one flavivirus gene, NS4A, uniquely determines the up-regulation of autophagy. Dengue-2 and Modoc (a murine flavivirus) kill primary murine macrophages but protect epithelial cells and fibroblasts against death provoked by several insults. The flavivirus-induced protection derives from the up-regulation of autophagy, as up-regulation of autophagy by starvation or inactivation of mammalian target of rapamycin also protects the cells against insult, whereas inhibition of autophagy via inactivation of PI3K nullifies the protection conferred by flavivirus. Inhibition of autophagy also limits replication of both Dengue-2 and Modoc virus in epithelial cells. Expression of flavivirus NS4A is sufficient to induce PI3K-dependent autophagy and to protect cells against death; expression of other viral genes, including NS2A and NS4B, fails to protect cells against several stressors. Flavivirus NS4A protein induces autophagy in epithelial cells and thus protects them from death during infection. As autophagy is vital to flavivirus replication in these cells, NS4A is therefore also identified as a critical determinant of flavivirus replication.