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Hepatitis C Virus Nonstructural 5B Protein Regulates Tumor Necrosis Factor Alpha Signaling through Effects on Cellular IB Kinase

Soo-Ho Choi,^1, Kyu-Jin Park,^1, Byung-Yoon Ahn,² Guhung Jung,³ Michael M. C. Lai,⁴ and Soon B. Hwang^1*

Ilsong Institute of Life Science, Hallym University, Chuncheon 200-702, South Korea,¹ School of Science and Biotechnology, Korea University, Seoul 136-701, South Korea,² School of Biological Sciences, Seoul National University, Seoul 151-742, South Korea,³ Department of Molecular Microbiology and Immunology, University of Southern California School of Medicine, Los Angeles, California 90033⁴

Received 13 June 2005/ Returned for modification 25 July 2005/ Accepted 23 January 2006

Hepatitis C virus (HCV) NS5B protein is a membrane-associated phosphoprotein that possesses an RNA-dependent RNA polymerase activity. We recently reported that NS5A protein interacts with TRAF2 and modulates tumor necrosis factor alpha (TNF-)-induced NF-B and Jun N-terminal protein kinase (JNK). Since NS5A and NS5B are the essential components of the HCV replication complex, we examined whether NS5B could modulate TNF--induced NF-B and JNK activation. In this study, we have demonstrated that TNF--induced NF-B activation is inhibited by NS5B protein in HEK293 and hepatic cells. Furthermore, NS5B protein inhibited both TRAF2- and IKK-induced NF-B activation. Using coimmunoprecipitation assays, we show that NS5B interacts with IKK. Most importantly, NS5B protein in HCV subgenomic replicon cells interacted with endogenous IKK, and then TNF--mediated IKK kinase activation was significantly decreased by NS5B. Using in vitro kinase assay, we have further found that NS5B protein synergistically activated TNF--mediated JNK activity in HEK293 and hepatic cells. These data suggest that NS5B protein modulates TNF- signaling pathways and may contribute to HCV pathogenesis.

These authors contributed equally to this work.

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