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J. Biol. Chem., Vol. 278, Issue 20, 17775-17784, May 16, 2003
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From the The hepatitis C virus nonstructural 5A (NS5A)
protein is a pleiotropic phosphoprotein that has been shown to
associate with a wide variety of cellular signaling proteins. Of
particular interest is the observation that a highly conserved
C-terminal Class II polyproline motif within NS5A mediated association
with the Src homology 3 domains of members of the Src family of
tyrosine kinases and the mitogenic adaptor protein Grb2 (A. Macdonald,
K. Crowder, A. Street, C. McCormick, and M. Harris, submitted
for publication). In this study, we analyzed the consequences of NS5A
expression on mitogenic signaling pathways within a variety of cell
lines. Utilizing a transient luciferase reporter system, we observed that NS5A inhibited the activity of the mitogenic and stress-activated transcription factor activating protein-1 (AP1). This inhibition was
dependent upon a Class II polyproline motif within NS5A. Using a
combination of dominant active and negative mutants of components of
the MAPK signaling pathways, selective inhibitors, together with
immunoblotting with phospho-specific and phosphorylation-independent antibodies, we determined the signaling pathways targeted by NS5A to
inhibit AP1. These studies demonstrated that in both stable NS5A-expressing cells and Huh-7-derived cells harboring subgenomic hepatitis C virus (HCV) replicons, this inhibition was mediated through
the ERK signaling pathway. Importantly, a comparable inhibition of AP1
reporter activity was observed in hepatocyte-derived cell lines
transduced with a baculovirus vector driving expression of full-length
HCV polyprotein. In conclusion, these data strongly suggest a role for
the NS5A protein in the perturbation of mitogenic signaling pathways in
HCV-infected hepatocytes.
The Hepatitis C Virus Non-structural NS5A Protein Inhibits
Activating Protein-1 Function by Perturbing Ras-ERK Pathway
Signaling*
,,§,,
Division of Microbiology, School of
Biochemistry and Molecular Biology, University of Leeds, Leeds, LS2
9JT, United Kingdom and the ¶ Institute of Medical Technology,
Tampere University Hospital, Tampere, Finland FIN-33014
*
This work was supported by British Medical Research Council
Grant G9801522 and a grant from the Wellcome Trust.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Division of
Microbiology, School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK. Tel.: 44-113-343-5632; Fax:
44-113-343-5638; E-mail: mharris@bmb.leeds.ac.uk.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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