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HCV NS3 protease enhances liver fibrosis via binding to and activating TGF-? 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)-? 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-?2 in (CAGA)9-Luc CCL64 cells and in human hepatic cell lines via binding to TGF-? type I receptor (T?RI). Tumor necrosis factor (TNF)-? facilitates this mechanism by increasing the colocalization of T?RI with NS3 protease on the surface of HCV-infected cells. An anti-NS3 antibody against computationally predicted binding sites for T?RI blocked the TGF-? mimetic activities of NS3 in vitro and attenuated liver fibrosis in HCV-infected chimeric mice. These data suggest that HCV NS3 protease mimics TGF-?2 and functions, at least in part, via directly binding to and activating T?RI, thereby enhancing liver fibrosis.

SUBMITTER: Sakata K

PROVIDER: S-EPMC3837337 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

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

Scientific reports 20131122

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). Tumo ...[more]

PMID: 24263861

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Project description:BACKGROUND:Hepatic fibrosis is caused by chronic liver injury and may progress toward liver cirrhosis, and even hepatocellular carcinoma. However, current treatment is not satisfactory. Therefore, there is a mandate to find novel therapeutic targets to improve therapy, and biomarkers to monitor therapeutic response. METHODS:Liver fibrosis was induced by carbon tetrachloride (CCl4) or thioacetamide (TAA) in wild type (WT) or CTHRC1-/- mice, followed by immunofluorescence and immunohistochemical analyses. CTHRC1 monoclonal antibody (mAb) was used to abrogate the effect of CTHRC1 in vitro and in vivo. RESULTS:Here, we reported that collagen triple helix repeat containing 1 (CTHRC1), a secreted protein derived from hepatic stellate cells (HSCs), was significantly up-regulated in fibrotic liver tissues. CTHRC1 promoted HSCs transformation from a quiescent to an activated state, and enhanced migratory or contractile capacities of HSCs by activating TGF-? signaling. Meanwhile, CTHRC1 competitively bound to Wnt noncononical receptor and promoted the contractility but not activation of HSCs. CCl4 or TAA-induced liver fibrosis was attenuated in CTHRC-/- mice compared with littermate control, while a monoclonal antibody of CTHRC1 suppressed liver fibrosis in WT mice treated with CCl4 or TAA. INTERPRETATION:We demonstrated that CTHRC1 is a new regulator of liver fibrosis by modulating TGF-? signaling. Targeting CTHRC1 could be a promising therapeutic approach, which can suppress TGF-? signaling and avoid the side effects caused by directly targeting TGF-?. CTHRC1 could also be a potential biomarker for monitoring response to anti-fibrotic therapy. FUND: This study was supported by the National Natural Science Foundation of China (ID 81672358, 81871923, 81872242, 81802890), the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (ID 20181708), the Natural Science Foundation of Shanghai (ID 17ZR1428300, 18ZR1436900), and Shanghai Municipal Health Bureau (ID 2018BR32). The funders did not play a role in manuscript design, data collection, data analysis, interpretation nor writing of the manuscript.

Dataset Information

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

Publications

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

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