Siu Gavin Ka Yu, Zhou Fan, Yu Mei Kuen, Zhang Leiliang, Wang Tuanlao, Liang Yongheng, Chen Yangchao, Chan Hsiao Chang, Yu Sidney
School of Biomedical Sciences and The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, P.R. China.
College of Life Sciences, Key Laboratory of Agricultural Environmental Microbiology of MOA, Nanjing Agricultural University, Nanjing 210095, China.
Sci Rep. 2016 Mar 24;6:23464. doi: 10.1038/srep23464.
Hepatitis C virus (HCV) has long been observed to take advantage of the host mitochondria to support viral replication and assembly. The HCV core protein has been implicated to fragment host mitochondria. In this report, we have discovered that the non-structural protein 5A (NS5A) plays an instructive role in attaching ER with mitochondria, causing mitochondrial fragmentation. Dynamin-related protein 1(Drp1), a host protein essential to mitochondrial membrane fission, does not play a role in NS5A-induced mitochondrial fragmentation. Instead, phosphatidylinositol 4-kinase IIIα (PI4KA), which has been demonstrated to bind to NS5A and is required to support HCV life cycle, is required for NS5A to induce mitochondrial fragmentation. Both NS5A and core are required by HCV to fragment the mitochondria, as inhibiting either of their respective downstream proteins, PI4KA or Drp1, resulted in lengthening of mitochondria tubules in HCVcc-infected cells. By fragmenting the mitochondria, NS5A renders the cells more resistant to mitochondria mediated apoptosis. This finding indicates previously-ignored contribution of NS5A in HCV-induced mitochondria dysfunction.
长期以来，人们观察到丙型肝炎病毒（HCV）利用宿主线粒体来支持病毒复制和组装。HCV核心蛋白被认为会使宿主线粒体碎片化。在本报告中，我们发现非结构蛋白5A（NS5A）在使内质网与线粒体相连从而导致线粒体碎片化过程中发挥指导作用。动力相关蛋白1（Drp1）是一种对线粒体膜裂变至关重要的宿主蛋白，在NS5A诱导的线粒体碎片化过程中不起作用。相反，已证明与NS5A结合且是支持HCV生命周期所必需的磷脂酰肌醇4激酶IIIα（PI4KA），是NS5A诱导线粒体碎片化所必需的。HCV需要NS5A和核心蛋白来使线粒体碎片化，因为抑制它们各自的下游蛋白PI4KA或Drp1会导致HCVcc感染细胞中的线粒体小管延长。通过使线粒体碎片化，NS5A使细胞对线粒体介导的凋亡更具抗性。这一发现表明NS5A在HCV诱导的线粒体功能障碍中存在先前被忽视的作用。
