title: Hepatitis C virus NS5A protein cooperates with phosphatidylinositol 4-kinase IIIα to induce mitochondrial fragmentation.
abstract: 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.
authors.affiliation: School of Biomedical Sciences and The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, P.R. China.
authors.forename: Gavin Ka Yu
authors.initials: GK
authors.lastname: Siu
authors.affiliation: College of Life Sciences, Key Laboratory of Agricultural Environmental Microbiology of MOA, Nanjing Agricultural University, Nanjing 210095, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhou
authors.affiliation: School of Biomedical Sciences and The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, P.R. China.|Epithelial Cell Biology Research Centre, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, P.R. China.
authors.forename: Mei Kuen
authors.initials: MK
authors.lastname: Yu
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100176, China.
authors.forename: Leiliang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Tuanlao
authors.initials: T
authors.lastname: Wang
authors.affiliation: College of Life Sciences, Key Laboratory of Agricultural Environmental Microbiology of MOA, Nanjing Agricultural University, Nanjing 210095, China.
authors.forename: Yongheng
authors.initials: Y
authors.lastname: Liang
authors.affiliation: School of Biomedical Sciences and The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, P.R. China.
authors.forename: Yangchao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Biomedical Sciences and The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, P.R. China.|Epithelial Cell Biology Research Centre, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, P.R. China.
authors.forename: Hsiao Chang
authors.initials: HC
authors.lastname: Chan
authors.affiliation: School of Biomedical Sciences and The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, P.R. China.|Epithelial Cell Biology Research Centre, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, P.R. China.
authors.forename: Sidney
authors.initials: S
authors.lastname: Yu
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008930:Mitochondria, Liver / Q000378:metabolism*; D011485:Protein Binding; D017361:Viral Nonstructural Proteins / Q000378:metabolism / Q000502:physiology*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D019870:1-Phosphatidylinositol 4-Kinase; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase