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J. Biol. Chem., Vol. 281, Issue 11, 7468-7478, March 17, 2006

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Modulation of the Transforming Growth Factor- Signal Transduction Pathway by Hepatitis C Virus Nonstructural 5A Protein^*

From the Ilsong Institute of Life Science, Hallym University, Chuncheon 200-702, Korea

Transforming growth factor- (TGF-) is implicated in the pathogenesis of liver disease. TGF- is involved both in liver regeneration and in the fibrotic and cirrhotic transformation with hepatitis viral infection. Hepatitis C virus (HCV) infection often leads to cirrhosis and hepatocellular carcinoma. HCV nonstructural 5A (NS5A) protein is a multifunctional protein that modulates cytokine-mediated signal transduction pathways. To elucidate the molecular mechanism of HCV pathogenesis, we examined the effect of NS5A protein on TGF--stimulated signaling cascades. We show that NS5A protein inhibited the TGF--mediated signaling pathway in hepatoma cell lines as determined by reporter gene assay. To further investigate the role of NS5A, we examined the protein/protein interaction between NS5A and TGF- signal transducers. Both in vitro and in vivo binding data showed that NS5A protein directly interacted with TGF- receptor I (TR-I) in hepatoma cell lines. This interaction was mapped to amino acids 148-238 of NS5A. We also found that NS5A protein co-localized with TR-I in the cytoplasm of Huh7 cells and inhibited TGF--mediated nuclear translocation of Smad2. Furthermore, we demonstrate that NS5A protein abrogated the phosphorylation of Smad2 and the heterodimerization of Smad3 and Smad4. To further explore the relevance to viral infection, we examined the effect of the HCV subgenomic replicon on the TGF- signaling pathway. We show that the HCV subgenomic replicon also inhibited TGF--induced signaling cascades. These results indicate that HCV NS5A modulates TGF- signaling through interaction with TR-I and that NS5A may be an important risk factor in HCV-associated liver pathogenesis.

Received for publication, November 21, 2005 , and in revised form, December 27, 2005.

^* This work was supported by Korea Research Foundation Grant KRF-2002-015-CP0308 and by Hallym University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Ilsong Inst. of Life Science, Hallym University, 1 Ockcheon-dong, Chuncheon 200-702, Korea. Tel.: 82-31-380-1732; Fax: 82-31-384-5395; E-mail: sbhwang{at}hallym.ac.kr.

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