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 re...

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Autores principales:	Saurabh Chattopadhyay, Volker Fensterl, Ying Zhang, Manoj Veleeparambil, Jaime L. Wetzel, Ganes C. Sen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c01906a0d1de483f9a7d3798980120bf
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spelling	oai:doaj.org-article:c01906a0d1de483f9a7d3798980120bf2021-11-15T15:40:29ZInhibition 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 Coactivators10.1128/mBio.00636-122150-7511https://doaj.org/article/c01906a0d1de483f9a7d3798980120bf2013-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00636-12https://doaj.org/toc/2150-7511ABSTRACT 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.Saurabh ChattopadhyayVolker FensterlYing ZhangManoj VeleeparambilJaime L. WetzelGanes C. SenAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 2 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Saurabh Chattopadhyay Volker Fensterl Ying Zhang Manoj Veleeparambil Jaime L. Wetzel Ganes C. Sen 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
description	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.
format	article
author	Saurabh Chattopadhyay Volker Fensterl Ying Zhang Manoj Veleeparambil Jaime L. Wetzel Ganes C. Sen
author_facet	Saurabh Chattopadhyay Volker Fensterl Ying Zhang Manoj Veleeparambil Jaime L. Wetzel Ganes C. Sen
author_sort	Saurabh Chattopadhyay
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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/c01906a0d1de483f9a7d3798980120bf
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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

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