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

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

Author information

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.

PMID:
24263861
PMCID:
PMC3837337
DOI:
10.1038/srep03243
[Indexed for MEDLINE]
Free PMC Article
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