Vesicular Stomatitis Virus Induces Apoptosis Primarily through Bak Rather than Bax by Inactivating Mcl-1 and Bcl-XL
Vesicular Stomatitis Virus Induces Apoptosis Primarily through Bak Rather than Bax by Inactivating Mcl-1 and Bcl-XL
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DOI：
10.1128/jvi.00436-09
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发表时间：
2009-09-15
影响因子：
5.4
通讯作者：
Lyles, Douglas S.
中科院分区：
文献类型：
--
作者：
Pearce, Alicia F.;Lyles, Douglas S.
水泡性口炎病毒（VSV）通过线粒体途径诱导细胞凋亡。线粒体途径由Bcl-2蛋白家族调节，该家族由促凋亡和抗凋亡成员组成。为了确定多结构域促凋亡Bcl-2家族成员巴克和Bax的相对重要性，用巴克和/或Bax小干扰RNA（siRNA）转染HeLa细胞，随后用重组野生型VSV感染。我们的研究结果表明，巴克是更重要的诱导凋亡比Bax在这个系统中。巴克受两种抗凋亡Bcl-2蛋白的调节，Mcl-1，其快速翻转，和Bcl-X-L，其相对稳定。VSV M蛋白对宿主基因表达的抑制导致Mcl-1的降解，而不是Bcl-X-L。然而，Mcl-1和Bcl-X-L的失活是细胞凋亡所必需的。虽然Mcl-1的失活是由于其表达的抑制，但Bcl-X-L的失活表明一个或多个仅BH 3的Bcl-2家族成员的作用。VSV诱导的细胞凋亡被抑制的siRNA转染对投标，BH 3-唯一的蛋白，通常被激活的caspase-8，与死亡受体途径相关的启动caspase的裂解。类似地，用半胱天冬酶-8抑制剂处理抑制VSV诱导的细胞凋亡。这些结果表明，在VSV激活线粒体途径中，来自死亡受体途径的串扰起作用。
Vesicular stomatitis virus (VSV) induces apoptosis via the mitochondrial pathway. The mitochondrial pathway is regulated by the Bcl-2 family of proteins, which consists of both pro- and antiapoptotic members. To determine the relative importance of the multidomain proapoptotic Bcl-2 family members Bak and Bax, HeLa cells were transfected with Bak and/or Bax small interfering RNA ( siRNA) and subsequently infected with recombinant wild-type VSV. Our results showed that Bak is more important than Bax for the induction of apoptosis in this system. Bak is regulated by two antiapoptotic Bcl-2 proteins, Mcl-1, which is rapidly turned over, and Bcl-X-L, which is relatively stable. Inhibition of host gene expression by the VSV M protein resulted in the degradation of Mcl-1 but not Bcl-X-L. However, inactivation of both Mcl-1 and Bcl-X-L was required for cells to undergo apoptosis. While inactivation of Mcl-1 was due to inhibition of its expression, inactivation of Bcl-X-L indicates a role for one or more BH3-only Bcl-2 family members. VSV-induced apoptosis was inhibited by transfection with siRNA against Bid, a BH3-only protein that is normally activated by the cleavage of caspase-8, the initiator caspase associated with the death receptor pathway. Similarly, treatment with an inhibitor of caspase-8 inhibited VSV-induced apoptosis. These results indicate a role for cross talk from the death receptor pathway in the activation of the mitochondrial pathway by VSV.