HCV NS3 protease enhances liver fibrosis via binding to and activating TGF-β type I receptor

Kotaro Sakata; Mitsuko Hara; Takaho Terada; Noriyuki Watanabe; Daisuke Takaya; So-ichi Yaguchi; Takehisa Matsumoto; Tomokazu Matsuura; Mikako Shirouzu; Shigeyuki Yokoyama; Tokio Yamaguchi; Keiji Miyazawa; Hideki Aizaki; Tetsuro Suzuki; Takaji Wakita; Masaya Imoto; Soichi Kojima

doi:10.1038/srep03243

HCV NS3 protease enhances liver fibrosis via binding to and activating TGF-β type I receptor

Sci Rep. 2013 Nov 22:3:3243. doi: 10.1038/srep03243.

Authors

Kotaro Sakata¹, Mitsuko Hara, Takaho Terada, Noriyuki Watanabe, Daisuke Takaya, So-ichi Yaguchi, Takehisa Matsumoto, Tomokazu Matsuura, Mikako Shirouzu, Shigeyuki Yokoyama, Tokio Yamaguchi, Keiji Miyazawa, Hideki Aizaki, Tetsuro Suzuki, Takaji Wakita, Masaya Imoto, Soichi Kojima

Affiliation

¹ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Antibodies / immunology
Binding Sites
Cell Line
Collagen Type I / metabolism
HEK293 Cells
Hepacivirus / enzymology*
Humans
Liver Cirrhosis / metabolism
Liver Cirrhosis / pathology*
Mice
Mice, SCID
Mice, Transgenic
Molecular Docking Simulation
Molecular Sequence Data
Protein Serine-Threonine Kinases / chemistry
Protein Serine-Threonine Kinases / metabolism*
Protein Structure, Tertiary
Receptor, Transforming Growth Factor-beta Type I
Receptors, Transforming Growth Factor beta / chemistry
Receptors, Transforming Growth Factor beta / metabolism*
Transforming Growth Factor beta1 / genetics
Transforming Growth Factor beta1 / metabolism
Transforming Growth Factor beta2 / genetics
Transforming Growth Factor beta2 / metabolism
Tumor Necrosis Factor-alpha
Viral Nonstructural Proteins / immunology
Viral Nonstructural Proteins / metabolism*

Substances

Antibodies
Collagen Type I
NS3 protein, hepatitis C virus
Receptors, Transforming Growth Factor beta
Transforming Growth Factor beta1
Transforming Growth Factor beta2
Tumor Necrosis Factor-alpha
Viral Nonstructural Proteins
Protein Serine-Threonine Kinases
Receptor, Transforming Growth Factor-beta Type I