Lack of Bax Prevents Influenza A Virus-Induced Apoptosis and Causes Diminished Viral Replication
Lack of Bax Prevents Influenza A Virus-Induced Apoptosis and Causes Diminished Viral Replication
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DOI：
10.1128/jvi.02672-08
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发表时间：
2009-08-15
影响因子：
5.4
通讯作者：
Zakeri, Zahra F.
中科院分区：
文献类型：
--
作者：
McLean, Jeffrey E.;Datan, Emmanuel;Zakeri, Zahra F.
Bcl-2的异位过表达限制了MDCK细胞中甲型流感病毒诱导的细胞凋亡和甲型流感病毒复制，从而表明Bcl-2家族成员在感染期间的作用。在这里，我们报告说，A型流感病毒不能建立一个凋亡反应没有功能Bax，Bcl-2的下游目标，Bax和巴克直接参与A型流感病毒复制和病毒诱导的细胞死亡。在甲型流感病毒感染MDCK细胞期间，巴克被显著下调，并且小鼠胚胎成纤维细胞中巴克的敲除导致细胞凋亡死亡率的显著上升和病毒复制水平的相应增加，这表明巴克抑制细胞凋亡和病毒复制，并且病毒抑制巴克。然而，Bax被激活并从细胞质易位到线粒体;这种激活是有效诱导细胞凋亡和病毒复制所必需的。敲除小鼠胚胎成纤维细胞中的Bax阻断了细胞凋亡的诱导，限制了感染介导的刽子手半胱天冬酶的激活，并抑制了病毒的繁殖。Bax敲除细胞仍然死亡，但通过显示自噬特征的替代死亡途径，类似于我们先前的观察，即在存在泛胱天蛋白酶抑制剂的情况下甲型流感病毒感染导致自噬水平增加。Bax的敲除导致甲型流感病毒NP保留在细胞核内。我们的结论是，细胞和病毒的斗争，以控制细胞凋亡和自噬，适当的时间凋亡是很重要的甲型流感病毒的复制。
The ectopic overexpression of Bcl-2 restricts both influenza A virus-induced apoptosis and influenza A virus replication in MDCK cells, thus suggesting a role for Bcl-2 family members during infection. Here we report that influenza A virus cannot establish an apoptotic response without functional Bax, a downstream target of Bcl-2, and that both Bax and Bak are directly involved in influenza A virus replication and virus-induced cell death. Bak is substantially downregulated during influenza A virus infection in MDCK cells, and the knockout of Bak in mouse embryonic fibroblasts yields a dramatic rise in the rate of apoptotic death and a corresponding increase in levels of virus replication, suggesting that Bak suppresses both apoptosis and the replication of virus and that the virus suppresses Bak. Bax, however, is activated and translocates from the cytosol to the mitochondria; this activation is required for the efficient induction of apoptosis and virus replication. The knockout of Bax in mouse embryonic fibroblasts blocks the induction of apoptosis, restricts the infection-mediated activation of executioner caspases, and inhibits virus propagation. Bax knockout cells still die but by an alternative death pathway displaying characteristics of autophagy, similarly to our previous observation that influenza A virus infection in the presence of a pancaspase inhibitor leads to an increase in levels of autophagy. The knockout of Bax causes a retention of influenza A virus NP within the nucleus. We conclude that the cell and virus struggle to control apoptosis and autophagy, as appropriately timed apoptosis is important for the replication of influenza A virus.