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

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Article number3243
JournalScientific Reports
Volume3
DOIs
Publication statusPublished - 2013

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Viral Structural Proteins
Growth Factor Receptors
Transforming Growth Factors
Hepacivirus
Liver Cirrhosis
Peptide Hydrolases
Proteins
Hepatocytes
Collagen
Tumor Necrosis Factor-alpha
Binding Sites
Viruses
Cell Line
Antibodies

ASJC Scopus subject areas

  • General

Cite this

Sakata, K., Hara, M., Terada, T., Watanabe, N., Takaya, D., Yaguchi, S. I., ... Kojima, S. (2013). HCV NS3 protease enhances liver fibrosis via binding to and activating TGF-β type i receptor. Scientific Reports, 3, [3243]. https://doi.org/10.1038/srep03243

HCV NS3 protease enhances liver fibrosis via binding to and activating TGF-β type i receptor. / Sakata, Kotaro; Hara, Mitsuko; Terada, Takaho; Watanabe, Noriyuki; Takaya, Daisuke; Yaguchi, So Ichi; Matsumoto, Takehisa; Matsuura, Tomokazu; Shirouzu, Mikako; Yokoyama, Shigeyuki; Yamaguchi, Tokio; Miyazawa, Keiji; Aizaki, Hideki; Suzuki, Tetsuro; Wakita, Takaji; Imoto, Masaya; Kojima, Soichi.

In: Scientific Reports, Vol. 3, 3243, 2013.

Research output: Contribution to journalArticle

Sakata, K, Hara, M, Terada, T, Watanabe, N, Takaya, D, Yaguchi, SI, Matsumoto, T, Matsuura, T, Shirouzu, M, Yokoyama, S, Yamaguchi, T, Miyazawa, K, Aizaki, H, Suzuki, T, Wakita, T, Imoto, M & Kojima, S 2013, 'HCV NS3 protease enhances liver fibrosis via binding to and activating TGF-β type i receptor', Scientific Reports, vol. 3, 3243. https://doi.org/10.1038/srep03243
Sakata, Kotaro ; Hara, Mitsuko ; Terada, Takaho ; Watanabe, Noriyuki ; Takaya, Daisuke ; Yaguchi, So Ichi ; Matsumoto, Takehisa ; Matsuura, Tomokazu ; Shirouzu, Mikako ; Yokoyama, Shigeyuki ; Yamaguchi, Tokio ; Miyazawa, Keiji ; Aizaki, Hideki ; Suzuki, Tetsuro ; Wakita, Takaji ; Imoto, Masaya ; Kojima, Soichi. / HCV NS3 protease enhances liver fibrosis via binding to and activating TGF-β type i receptor. In: Scientific Reports. 2013 ; Vol. 3.
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