title: Protein phosphatase 2A impairs IFNα-induced antiviral activity against the hepatitis C virus through the inhibition of STAT1 tyrosine phosphorylation.
abstract: Mammalian cells have developed several mechanisms to sense viruses and initiate adequate responses such as production of interferons. Interferons activate the antiviral response through the Jak-STAT signalling pathway. To establish a chronic infection, viruses need to counteract this barrier of defence. The hepatitis C and hepatitis B viruses are known to up-regulate the expression of protein phosphatase 2A (PP2A). In this study, we show that PP2Ac associates with Jak1/Tyk2/STAT1 and reduces Jak1/Tyk2/STAT1 phosphorylation resulting in an impairment of the IFNα-induced HCV antiviral response. Using the fully infectious HCV cell culture system (HCVcc), we demonstrate that the PP2A catalytic activity is not required to block the antiviral effect of IFNα, although it is needed to support HCVcc replication. Our data suggest an important contribution of virus-induced PP2Ac up-regulation in the establishment of a chronic infection.
authors.affiliation: Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Shanker
authors.forename: G
authors.initials: G
authors.lastname: Trincucci
authors.forename: H M
authors.initials: HM
authors.lastname: Heim
authors.forename: H T F
authors.initials: HT
authors.lastname: Duong
mesh_terms: D000818:Animals; D002460:Cell Line; D016174:Hepacivirus / Q000276:immunology*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors*; D008297:Male; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014443:Tyrosine; D054648:Protein Phosphatase 2
keywords: HCV replication; STAT1; antiviral activity; interferon α; protein phosphatase 2A