Journal Article

PreJuSER-15093

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png C-Src is required for complex formation between the hepatitis C virus–encoded proteins NS5A and NS5B: A prerequisite for replication

Pfannkuche, A.FZJ* ; Büther, K.FZJ* ; Karthe, J.FZJ* ; Poenisch, M.FZJ* ; Bartenschlager, R.FZJ* ; Trilling, M.FZJ* ; Hengel, H.FZJ* ; Willbold, D.FZJ* ; Häussinger, D.FZJ* ; Bode, J. G.FZJ*

2011
Wiley Interscience New York [u.a.]

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Please use a persistent id in citations: doi:10.1002/hep.24214

Abstract: Hepatitis C virus (HCV) is a leading cause of chronic liver disease worldwide and establishes a persistent infection in more than 60% of infected individuals. This high frequency of persistent infection indicates that HCV has evolved efficient strategies to interfere with the adaptive and innate immune response and to occupy and use host cell infrastructure. The present study provides evidence that c-Src, a member of the Src family kinases that participates in many signal transduction pathways, represents an essential host factor exploited for viral replication. c-Src directly interacts with the viral RNA-dependent RNA polymerase (NS5B) via its SH3 domain and with the nonstructural phosphoprotein NS5A via its SH2 domain. Both interactions are required to maintain the protein-protein interaction of NS5A and NS5B, which has been previously demonstrated to be essential for viral replication. Accordingly, HCV genome replication and production of the viral proteins was strongly reduced upon small interfering RNA-mediated knockdown of c-Src or in the presence of the tyrosine kinase inhibitor herbimycin A. This effect could not be rescued by supplementation of the two other ubiquitously expressed Src family kinases Fyn or Yes. CONCLUSION: Our data suggest that c-Src participates in the formation of an NS5A/NS5B protein complex that is required for efficient replication of HCV.

Keyword(s): Benzoquinones: pharmacology (MeSH) ; Cell Line, Tumor (MeSH) ; Hepacivirus: genetics (MeSH) ; Hepacivirus: physiology (MeSH) ; Humans (MeSH) ; Lactams, Macrocyclic: pharmacology (MeSH) ; RNA Replicase: genetics (MeSH) ; Viral Nonstructural Proteins (MeSH) ; Virus Replication (MeSH) ; src Homology Domains: genetics (MeSH) ; src-Family Kinases: physiology (MeSH) ; Benzoquinones ; Lactams, Macrocyclic ; NS-5 protein, hepatitis C virus ; Viral Nonstructural Proteins ; herbimycin ; src-Family Kinases ; RNA Replicase ; J

Note: Supported by the German Research Foundation through the following grants: FOR 729 (Teilprojekt 7 to J. B. and D. H.), SFB 575, and GK 1045 and SFB 638 (Teilprojekt 5 to R. B.). M. P. is supported by the Postdoc Fellowship of the Medical Faculty of Heidelberg. J. B. is supported by the Heisenberg Program of the German Research Foundation.

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Contributing Institute(s):

1. Strukturbiochemie (ICS-6)

Research Program(s):

1. Funktion und Dysfunktion des Nervensystems (P33)
2. BioSoft: Makromolekulare Systeme und biologische Informationsverarbeitung (P45)

Appears in the scientific report 2011

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