Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence
Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence
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DOI：
10.1073/pnas.1321114111
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发表时间：
2014-04-29
影响因子：
11.1
通讯作者：
Siddiqui, Aleem
中科院分区：
文献类型：
--
作者：
Kim, Seong-Jun;Syed, Gulam H.;Siddiqui, Aleem
线粒体动力学对于调节细胞内稳态是至关重要的。我们最近的研究结果表明，丙型肝炎病毒（HCV）促进帕金森介导的消除受损的线粒体（线粒体自噬）。在这里，我们表明，丙型肝炎病毒通过促进线粒体分裂，然后通过线粒体自噬，从而减弱丙型肝炎病毒诱导的细胞凋亡，扰乱线粒体动力学。HCV感染刺激动力蛋白相关蛋白1（Drp 1）及其线粒体受体，线粒体分裂因子的表达。HCV进一步诱导Drp 1（Ser 616）的磷酸化，并导致其随后易位到线粒体，随后发生线粒体自噬。干扰HCV诱导的线粒体分裂和线粒体自噬的Drp 1沉默抑制HCV分泌，伴随着细胞糖酵解和ATP水平的降低，以及增强先天免疫信号。更重要的是，沉默Drp 1或帕金引起细胞凋亡信号的显着增加，证明增加细胞色素C从线粒体释放，半胱天冬酶3活性，和裂解的聚（ADP-核糖）聚合酶。这些结果表明，HCV诱导的线粒体分裂和线粒体自噬服务，以减弱细胞凋亡，并可能有助于持续HCV感染。
Mitochondrial dynamics is crucial for the regulation of cell homeostasis. Our recent findings suggest that hepatitis C virus (HCV) promotes Parkin-mediated elimination of damaged mitochondria (mitophagy). Here we show that HCV perturbs mitochondrial dynamics by promoting mitochondrial fission followed by mitophagy, which attenuates HCV-induced apoptosis. HCV infection stimulated expression of dynamin-related protein 1 (Drp1) and its mitochondrial receptor, mitochondrial fission factor. HCV further induced the phosphorylation of Drp1 (Ser616) and caused its subsequent translocation to the mitochondria, followed by mitophagy. Interference of HCV-induced mitochondrial fission and mitophagy by Drp1 silencing suppressed HCV secretion, with a concomitant decrease in cellular glycolysis and ATP levels, as well as enhanced innate immune signaling. More importantly, silencing Drp1 or Parkin caused significant increase in apoptotic signaling, evidenced by increased cytochrome C release from mitochondria, caspase 3 activity, and cleavage of poly(ADP-ribose) polymerase. These results suggest that HCV-induced mitochondrial fission and mitophagy serve to attenuate apoptosis and may contribute to persistent HCV infection.