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Journal of Virology, September 2002, p. 9207-9217, Vol. 76, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.18.9207-9217.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Subversion of Cell Signaling Pathways by Hepatitis C Virus Nonstructural 5A Protein via Interaction with Grb2 and P85 Phosphatidylinositol 3-Kinase

Yupeng He,1 Haruhisa Nakao,1,{dagger} Seng-Lai Tan,1,{ddagger} Stephen J. Polyak,1,2 Petra Neddermann,3 Sangeetha Vijaysri,4 Bertram L. Jacobs,4,5 and Michael G. Katze1,6*

Department of Microbiology, School of Medicine,1 Regional Primate Research Center,6 Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195,2 Department of Microbiology,4 Graduate Degree Program in Molecular and Cellular Biology, Arizona State University, Tempe, Arizona 85287,5 Istituto di Ricerche di Biologia Molecolare P. Angeletti, Pomezia, Rome, Italy3

Received 9 April 2002/ Accepted 24 June 2002

Hepatitis C virus (HCV) sets up a persistent infection in patients that likely involves a complex virus-host interaction. We previously found that the HCV nonstructural 5A (NS5A) protein interacts with growth factor receptor-binding protein 2 (Grb2) adaptor protein and inhibits the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) by epidermal growth factor (EGF). In the present study, we extended this analysis and investigated the specificity of the Grb2-NS5A interaction and whether the subversion of mitogenic signaling involves additional pathways. NS5A containing mutations within the C-terminal proline-rich motif neither bound Grb2 nor inhibited ERK1/2 activation by EGF, demonstrating that NS5A-Grb2 binding and downstream effects were due to direct interactions. Interestingly, NS5A could also form a complex with the Grb2-associated binder 1 (Gab1) protein in an EGF treatment-dependent manner. However, the NS5A-Gab1 association, which appeared indirect, was not mediated by direct NS5A-Grb2 interaction but was likely dependent on direct NS5A interaction with the p85 subunit of phosphatidylinositol 3-kinase (PI3K). The in vivo association of NS5A with p85 PI3K required the N-terminal, but not the C-terminal, region of NS5A. The downstream effects of the NS5A-p85 PI3K interaction included increased tyrosine phosphorylation of p85 PI3K in response to EGF. Consistent with this observation and the antiapoptotic properties of NS5A, we also detected enhanced tyrosine phosphorylation of the downstream AKT protein kinase and increased serine phosphorylation of BAD, a proapoptotic factor and an AKT substrate, in the presence of NS5A. These results collectively suggest a model in which NS5A interacts with Grb2 to inhibit mitogenic signaling while simultaneously promoting the PI3K-AKT cell survival pathway by interaction with p85 PI3K, which may represent a crucial step in HCV persistence and pathogenesis.

* Corresponding author. Mailing address: Department of Microbiology, Box 358070, University of Washington, Seattle, WA 98195. Phone: (206) 732-6135. Fax: (206) 732-6055. E-mail: honey{at}u.washington.edu.

{dagger} Present address: First Department of Internal Medicine, Medical School, Nagoya City University, Mizuho-ku, Nagoya, Aichi 467-8601, Japan.

{ddagger} Present address: Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN 46285.

Journal of Virology, September 2002, p. 9207-9217, Vol. 76, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.18.9207-9217.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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