title: PKC alpha regulates Sendai virus-mediated interferon induction through HDAC6 and β-catenin.
abstract: Recognition of viral RNA by cytoplasmic retinoic acid inducible gene I (RIG-I)-like receptors initiates signals leading to the induction of type I interferon (IFN) transcription via transcription factors such as interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB). Here, we describe a new signalling pathway that involves protein kinase C alpha (PKCα), histone deacetylase 6 (HDAC6) and beta-catenin (β-catenin), which is essential for IFN gene induction following virus infection. Knockdown of PKCα in various human cells, including primary cells, inhibited Sendai virus (SeV)-mediated IFN induction and enhanced virus replication. In the absence of this pathway IRF3 becomes activated, but does not bind to its promoter and is thus unable to support transcription. Mechanistically, SeV infection induced the activation of PKCα, which promoted its interaction with HDAC6 and enhanced its deacetylation activity in a phosphorylation-dependent manner. Further downstream, HDAC6 caused deacetylation of β-catenin and enhanced its nuclear translocation and promoter binding. In the nucleus, β-catenin acted as a co-activator for IRF3-mediated transcription. Our findings suggest an important role of a novel signalling pathway mediated by PKCα-HDAC6-β-catenin in controlling IRF3-mediated transcription.
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Zhu
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Coyne
authors.forename: Saumendra N
authors.initials: SN
authors.lastname: Sarkar
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D029082:Sendai virus / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014779:Virus Replication; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051176:beta Catenin; D051571:Protein Kinase C-alpha; D006655:Histone Deacetylases