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.

Zebrafish IRF1, IRF3, and IRF7 Differentially Regulate IFNΦ1 and IFNΦ3 Expression through Assembly of Homo- or Heteroprotein Complexes

“…The exact causes of such a phenomenon are unknown, but it is possible that a misfolded protein conformation in in vitro-translated IRF3 restricts its binding to IFN promoters. Notably, in vivo assays showed that, in mammals, IRF3 binding to target gene promoters requires the activation of two coactivators, b-catenin and CBP, by HDAC6 and PKC-b (50). Therefore, it is important to analyze in vivo binding of fish IRF3 to IFN promoters in the future.…”

Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema

“…Interestingly, ␣-tubulin and ␤-catenin are endogenous substrates of HDAC6 (5,21,22,27,30). HDAC6-deficient mice are less vulnerable to endotoxininduced acute inflammation (9). However, the effects of HDAC6 inhibition on lung endothelial cell barrier function and the underlying mechanisms remain to be determined.…”

Fine-Tuning of the RIG-I-Like Receptor/Interferon Regulatory Factor 3-Dependent Antiviral Innate Immune Response by the Glycogen Synthase Kinase 3/β-Catenin Pathway

“…C-terminal phosphorylation of IRF3 by the IB kinase (IKK)-related kinases TANK-binding kinase 1 (TBK1) and IKKi (4,5) results in its dimerization and interaction with the transcriptional coactivators CREB-binding protein (CBP)/p300, which are required for the DNA binding activity of IRF3 to induce type I IFNs and selected sets of IRF3-regulated IFN-stimulated genes (ISGs) such as those for ISG54 (Ifit2), ISG56 (Ifit1), and viperin (Rsad2) (6). Recently, ␤-catenin has also been reported to act as a coactivator of IFN-␤ transcription allowing the recruitment of the acetyltransferase CBP/p300 to IRF3 (7)(8)(9). IRF3 and its coactivators are subject to positive or negative regulation by posttranslational modifications, protein phosphorylation being the most common (9)(10)(11).…”