title: Inhibition of viral pathogenesis and promotion of the septic shock response to bacterial infection by IRF-3 are regulated by the acetylation and phosphorylation of its coactivators.
abstract: Interferon (IFN) is required for protecting mice from viral pathogenesis; reciprocally, it mediates the deleterious septic shock response to bacterial infection. The critical transcription factor for IFN induction, in both cases, is IRF-3, which is activated by TLR3 or RIG-I signaling in response to virus infection and TLR4 signaling in response to bacterial infection. Here, we report that IRF-3's transcriptional activity required its coactivators, β-catenin and CBP, to be modified by HDAC6-mediated deacetylation and protein kinase C isozyme β (PKC-β)-mediated phosphorylation, respectively, so that activated nuclear IRF-3 could form a stable transcription initiation complex at the target gene promoters. β-Catenin bridges IRF-3 and CBP, and the modifications were required specifically for the interaction between β-catenin and CBP but not β-catenin and IRF-3. Consequently, like IRF-3(-/-) mice, HDAC6(-/-) mice were resistant to bacterial lipopolysaccharide-induced septic shock. Conversely, they were highly susceptible to pathogenesis caused by Sendai virus infection. Thus, HDAC6 is an essential component of the innate immune response to microbial infection.
authors.affiliation: Department of Molecular Genetics, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: Volker
authors.initials: V
authors.lastname: Fensterl
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Manoj
authors.initials: M
authors.lastname: Veleeparambil
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Wetzel
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
mesh_terms: D000107:Acetylation; D000818:Animals; D001424:Bacterial Infections / Q000276:immunology*; D050882:CREB-Binding Protein / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D011499:Protein Processing, Post-Translational; D029082:Sendai virus / Q000276:immunology*; D012772:Shock, Septic; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D050838:Interferon Regulatory Factor-3; D051176:beta Catenin; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases