@article{f6fdec063abe4beda409ffb812bc1c35,
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.",
author = "Kotaro Sakata and Mitsuko Hara and Takaho Terada and Noriyuki Watanabe and Daisuke Takaya and Yaguchi, {So Ichi} and Takehisa Matsumoto and Tomokazu Matsuura and Mikako Shirouzu and Shigeyuki Yokoyama and Tokio Yamaguchi and Keiji Miyazawa and Hideki Aizaki and Tetsuro Suzuki and Takaji Wakita and Masaya Imoto and Soichi Kojima",
note = "Funding Information: We are indebted to Mr. Kazushige Katsura and Ms. Chiemi Mishima-Tsumagari (RIKEN Systems and Structural Biology Center, Kanagawa, Japan; Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Japan) for preparing and providing recombinant NS3, and Dr. Takashi Shimada, Dr. Chise Tateno, and Dr. Masakazu Kakuni (PhenixBio Co., Ltd., Hiroshima, Japan) for helpful discussions regarding the animal experiment. This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (23390202 to S.K.), and Grants for Collaborative Researchers from Industries (to K.S.), Program for Drug Discovery and Medical Technology Platforms (to S.K.), and Chemical Genomics Research Program (to S.K.) from RIKEN.",
year = "2013",
doi = "10.1038/srep03243",
language = "English",
volume = "3",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
}