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Journal of Virology, April 2005, p. 5006-5016, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.5006-5016.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus NS5A-Mediated Activation of Phosphoinositide 3-Kinase Results in Stabilization of Cellular ß-Catenin and Stimulation of ß-Catenin-Responsive Transcription

Andrew Street,{dagger} Andrew Macdonald,{dagger},{ddagger} Christopher McCormick, and Mark Harris*

School of Biochemistry and Microbiology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom

Received 7 September 2004/ Accepted 3 January 2005

The hepatitis C virus (HCV) nonstructural NS5A protein has been shown to bind to and activate phosphoinositide 3-kinase (PI3K), resulting in activation of the downstream effector serine/threonine kinase Akt/protein kinase B. Here we present data pertaining to the effects of NS5A-mediated Akt activation on its downstream targets. Using a recombinant baculovirus to deliver the complete HCV polyprotein to human hepatoma cells in a tetracycline-regulable fashion, we confirm that expression of the complete HCV polyprotein also activates PI3K and Akt. We further show that this results in the inhibition of the Akt substrate Forkhead transcription factor and the stimulation of phosphorylation of a second key Akt substrate, glycogen synthase kinase-3ß (GSK-3ß). Phosphorylation of GSK-3ß results in its inactivation; consistent with this, we show that expression of the HCV polyprotein results in the accumulation of ß-catenin. Finally, we show that levels of ß-catenin-dependent transcription are also elevated in the presence of the HCV polyprotein. Given the prevalence of ß-catenin mutations in many human tumors, especially colon and hepatocellular carcinomas, these data implicate NS5A-mediated PI3K activation as a contributory factor in the increasingly common association between HCV infection and the development of hepatocellular carcinoma.

* Corresponding author. Mailing address: School of Biochemistry and Microbiology, University of Leeds, Leeds LS2 9JT, United Kingdom. Phone: 44 (113) 343-5632. Fax: 44 (113) 343-5638. E-mail: m.harris{at}leeds.ac.uk.

{dagger} A.S. and A.M. contributed equally to this work.

{ddagger} Present address: MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.

Journal of Virology, April 2005, p. 5006-5016, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.5006-5016.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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