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 Article (Web of Science)

abstract

  • 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. IMPORTANCE It is important to understand how we protect ourselves against microbial infection. Specific receptors present in mammalian cells, called Toll-like receptors, are assigned to sense different microbial chemicals, such as bacterial lipopolysaccharides or viral double-stranded RNA. Activation of these receptors leads to the activation of a critical transcription factor, IRF-3, which drives the induced synthesis of interferon, a secreted protein required for our protection. Here, we report that interferon synthesis is regulated not only by IRF-3 activation but also by activation of two proteins, β-catenin and CBP, which function together with IRF-3. β-Catenin is activated by its deacetylation by HDAC6, and CBP is activated by its phosphorylation by protein kinases C isozyme β (PKC-β). These regulations are operative not only in cell cultures but also in mice.

authors

  • Fensterl, Volker
  • Zhang, Ying
  • Veleeparambil, Manoj
  • Wetzel, Jaime L.
  • Sen, Ganes C.

publication date

  • 2013

webpage

published in

volume

  • 4

issue

  • 2