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Journal of Virology, September 2006, p. 9226-9235, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.00459-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus Core Protein Blocks Interferon Signaling by Interaction with the STAT1 SH2 Domain

Wenyu Lin,1 Sun Suk Kim,1 Elaine Yeung,1 Yoshitaka Kamegaya,1 Jason T. Blackard,1 Kyung Ah Kim,1 Michael J. Holtzman,2 and Raymond T. Chung1*

Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114,1 Department of Medicine and Cell Biology, Washington University School of Medicine, St. Louis, Missouri 631102

Received 5 March 2006/ Accepted 26 June 2006

Emerging data have indicated that hepatitis C virus (HCV) subverts the host antiviral response to ensure its persistence. We previously demonstrated that HCV protein expression suppresses type I interferon (IFN) signaling by leading to the reduction of phosphorylated STAT1 (P-STAT1). We also demonstrated that HCV core protein directly bound to STAT1. However, the detailed mechanisms by which HCV core protein impacts IFN signaling components have not been fully clarified. In this report, we show that the STAT1 interaction domain resides in the N-terminal portion of HCV core (amino acids [aa] 1 to 23). This domain is also required to produce P-STAT1 reduction and inhibit IFN signaling transduction. Conversely, the C-terminal region of STAT1, specifically the SH2 domain (aa 577 to 684), is required for the interaction of HCV core with STAT1. The STAT1 SH2 domain is critical for STAT1 hetero- or homodimerization. We propose a model by which the binding of HCV core to STAT1 results in decreased P-STAT, blocked STAT1 heterodimerization to STAT2, and, therefore, reduced IFN-stimulated gene factor-3 binding to DNA and disrupted IFN-stimulated gene transcription.

* Corresponding author. Mailing address: GI Unit, GRJ 825, Massachusetts General Hospital, Boston, MA 02114. Phone: (617) 724-7562. Fax: (617) 726-5895. E-mail: rtchung{at}partners.org.

Journal of Virology, September 2006, p. 9226-9235, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.00459-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lukens, J. R., Cruise, M. W., Lassen, M. G., Hahn, Y. S. (2008). Blockade of PD-1/B7-H1 Interaction Restores Effector CD8+ T Cell Responses in a Hepatitis C Virus Core Murine Model. J. Immunol. 180: 4875-4884 [Abstract] [Full Text]  
  • Sillanpaa, M., Kaukinen, P., Melen, K., Julkunen, I. (2008). Hepatitis C virus proteins interfere with the activation of chemokine gene promoters and downregulate chemokine gene expression. J. Gen. Virol. 89: 432-443 [Abstract] [Full Text]  
  • Randall, R. E., Goodbourn, S. (2008). Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J. Gen. Virol. 89: 1-47 [Abstract] [Full Text]  


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