title: HCV NS3 protease enhances liver fibrosis via binding to and activating TGF-β type I receptor.
abstract: Viruses sometimes mimic host proteins and hijack the host cell machinery. Hepatitis C virus (HCV) causes liver fibrosis, a process largely mediated by the overexpression of transforming growth factor (TGF)-β and collagen, although the precise underlying mechanism is unknown. Here, we report that HCV non-structural protein 3 (NS3) protease affects the antigenicity and bioactivity of TGF-β2 in (CAGA)9-Luc CCL64 cells and in human hepatic cell lines via binding to TGF-β type I receptor (TβRI). Tumor necrosis factor (TNF)-α facilitates this mechanism by increasing the colocalization of TβRI with NS3 protease on the surface of HCV-infected cells. An anti-NS3 antibody against computationally predicted binding sites for TβRI blocked the TGF-β mimetic activities of NS3 in vitro and attenuated liver fibrosis in HCV-infected chimeric mice. These data suggest that HCV NS3 protease mimics TGF-β2 and functions, at least in part, via directly binding to and activating TβRI, thereby enhancing liver fibrosis.
authors.affiliation: 1] Micro-signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, Saitama 351-0198, Japan [2] Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Kanagawa 223-8522, Japan [3] Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd., Hiroshima 739-1195, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Sakata
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Hara
authors.forename: Takaho
authors.initials: T
authors.lastname: Terada
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Watanabe
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takaya
authors.forename: So-ichi
authors.initials: S
authors.lastname: Yaguchi
authors.forename: Takehisa
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Matsuura
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Tokio
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyazawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Aizaki
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.forename: Masaya
authors.initials: M
authors.lastname: Imoto
authors.forename: Soichi
authors.initials: S
authors.lastname: Kojima
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001665:Binding Sites; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D057809:HEK293 Cells; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha; D017361:Viral Nonstructural Proteins / Q000276:immunology / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000906:Antibodies; D024042:Collagen Type I; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D014409:Tumor Necrosis Factor-alpha; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases