Hepatitis C Virus Infection Induces Apoptosis through a Bax-Triggered, Mitochondrion-Mediated, Caspase 3-Dependent Pathway
Hepatitis C Virus Infection Induces Apoptosis through a Bax-Triggered, Mitochondrion-Mediated, Caspase 3-Dependent Pathway
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DOI：
10.1128/jvi.00395-08
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发表时间：
2008-11-01
影响因子：
5.4
通讯作者：
Hotta, Hak
中科院分区：
文献类型：
--
作者：
Deng, Lin;Adachi, Tetsuya;Hotta, Hak
我们之前报道过，含有丙型肝炎病毒（HCV）RNA复制子的细胞以及表达HCV NS3/4A的细胞表现出对次优剂量的细胞凋亡刺激的敏感性增加，以经历线粒体介导的细胞凋亡（Y.Nomura-Takikawa等人，J.Gen.Virol.87：1935-1945，2006）。然而，人们对HCV感染是否会诱导病毒感染细胞的凋亡知之甚少。本研究利用HCV基因型2a的嵌合J6/JFH1株，证明HCV感染可诱导Huh7.5细胞死亡。细胞死亡与 caspase 3 的激活、激活的 caspase 3 的核转位以及 DNA 修复酶聚（ADP-核糖）聚合酶的裂解有关，已知聚（ADP-核糖）聚合酶是激活的 caspase 3 的重要底物。这些结果表明，HCV 诱导的细胞死亡实际上是细胞凋亡。此外，HCV 感染激活了 Bax（Bcl-2 家族的促凋亡成员），其构象变化及其在线粒体膜上积累的增加表明了这一点。与此同时，HCV 感染诱导线粒体跨膜电位破坏，随后线粒体肿胀并从线粒体释放细胞色素 c。 HCV 感染还通过增加线粒体超氧化物的产生而引起氧化应激。另一方面，HCV 感染不会介导葡萄糖调节蛋白 78 (GRP78) 或 GRP94 的表达增加，这些蛋白被称为内质网 (ER) 应激诱导蛋白。这一结果表明，在我们的实验系统中，ER 应激并不主要参与 HCV 诱导的细胞凋亡。综上所述，我们目前的结果表明，HCV 感染通过 Bax 触发、线粒体介导、Caspase 3 依赖性途径诱导宿主细胞凋亡。
We previously reported that cells harboring the hepatitis C virus (HCV) RNA replicon as well as those expressing HCV NS3/4A exhibited increased sensitivity to suboptimal doses of apoptotic stimuli to undergo mitochondrion-mediated apoptosis (Y. Nomura-Takigawa, et al., J. Gen. Virol. 87: 1935-1945, 2006). Little is known, however, about whether or not HCV infection induces apoptosis of the virus-infected cells. In this study, by using the chimeric J6/JFH1 strain of HCV genotype 2a,we demonstrated that HCV infection induced cell death in Huh7.5 cells. The cell death was associated with activation of caspase 3, nuclear translocation of activated caspase 3, and cleavage of DNA repair enzyme poly(ADP-ribose) polymerase, which is known to be an important substrate for activated caspase 3. These results suggest that HCV-induced cell death is, in fact, apoptosis. Moreover, HCV infection activated Bax, a proapoptotic member of the Bcl-2 family, as revealed by its conformational change and its increased accumulation on mitochondrial membranes. Concomitantly, HCV infection induced disruption of mitochondrial transmembrane potential, followed by mitochondrial swelling and release of cytochrome c from mitochondria. HCV infection also caused oxidative stress via increased production of mitochondrial superoxide. On the other hand, HCV infection did not mediate increased expression of glucose-regulated protein 78 (GRP78) or GRP94, which are known as endoplasmic reticulum (ER) stress-induced proteins; this result suggests that ER stress is not primarily involved in HCV-induced apoptosis in our experimental system. Taken together, our present results suggest that HCV infection induces apoptosis of the host cell through a Bax-triggered, mitochondrion-mediated, caspase 3-dependent pathway(s).