title: A single-amino-acid mutation in hepatitis C virus NS5A disrupts physical and functional interaction with the transcription factor HNF-1α.
abstract: Hepatitis C virus (HCV) infection often causes extrahepatic manifestations, such as type 2 diabetes. We previously reported that HCV infection induces the lysosomal degradation of the transcription factor HNF-1α via an interaction with viral NS5A, thereby suppressing GLUT2 gene expression. However, the molecular mechanism of NS5A-induced degradation of HNF-1α is largely unknown. We aimed to identify the determinants necessary for the degradation of HNF-1α induced by NS5A. Coimmunoprecipitation analysis revealed that the POU specific (POUs) domain spanning from aa 91 to 181 of HNF-1α is responsible for the interaction of NS5A. We also found that the region from aa 121 to 126 of NS5A, which is known as the binding motif of the HCV replication factor FKBP8, is important for the degradation of HNF-1α. A NS5A V121A mutation disrupted the NS5A-HNF-1α interaction as well as the degradation of HNF-1α. Our findings suggest that NS5A Val121 is crucial for viral pathogenesis.
authors.affiliation: Division of Microbiology, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Matsui
authors.affiliation: Division of Microbiology, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.|Department of Physiology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
authors.forename: Imelda
authors.initials: I
authors.lastname: Rosalyn Sianipar
authors.affiliation: Division of Microbiology, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Nanae
authors.initials: N
authors.lastname: Minami
authors.affiliation: Division of Microbiology, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Lin
authors.initials: L
authors.lastname: Deng
authors.affiliation: Division of Microbiology, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Hak
authors.initials: H
authors.lastname: Hotta
authors.affiliation: Division of Microbiology, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Shoji
mesh_terms: D016174:Hepacivirus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020125:Mutation, Missense; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase