The protein phosphatase 2A represents a novel cellular target for hepatitis C virus NS5A protein.
It is well established that HCV NS5A protein when expressed in mammalian cells perturbs the extracellular signal regulated kinase (ERK) pathway. The protein serine/threonine phosphatase 2A controls the phosphorylation of numerous proteins involved in cell signaling and one characterized function is the regulation of Ras-Raf mitogen activated protein (MAP) kinase signaling pathways. Our results showed that expression of HCV NS5A protein stimulates phosphatase 2A (PP2A) activity in cells, indicating the relevance of NS5A as a regulator of PP2A in vivo. We found that transient expression of the full length NS5A protein in different cell lines leads to a significant increase of the PP2A activity and this activity is specifically inhibited by the addition of okadaic acid, a PP2A inhibitor, in living cells. Further investigation showed that NS5A protein interacts in vivo and in vitro with the scaffolding A and the catalytic C subunits of PP2A. We propose that HCV NS5A represents a viral PP2A regulatory protein. This is a novel function for the NS5A protein which may have a key role in the ability of the virus to deregulate cell growth and survival.
Georgopoulou
Urania
U
Molecular Virology Laboratory, Hellenic Pasteur Institute, 127, Vas. Sofias Avenue, Athens 11521, Greece. uraniag@mail.pasteur.gr
Tsitoura
Panagiota
P
Kalamvoki
Maria
M
Mavromara
Penelope
P
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D000882:Haplorhini; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D054648:Protein Phosphatase 2; D021122:Protein Subunits / Q000378:metabolism; D013379:Substrate Specificity; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase
D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D021122:Protein Subunits; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase