Histone deacetylase 3 contributes to the anti-viral innate immunity of macrophages through interacting with FOXK1 to regulate STAT1 and STAT2
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE190579 | GEO | 2022/05/12
REPOSITORIES: GEO
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Project description:It is well known that IFNα/β activates the JAK/STAT signaling pathway and suppresses viral replication through induction of interferon stimulated genes (ISGs). Here we reported that knockout of HDAC3 from macrophages resulted in decreased expression of STAT1 and STAT2, leading to a defective anti-viral immunity in cells and mice. Further studies showed that HDAC3 interacted with a conserved transcription factor Forkhead Box K1 (FOXK1), co-localized with FOXK1 at the promoter of STAT1 and STAT2, and was required for protecting FOXK1 from lysosomal system mediated degradation. Constantly, FOXK1 deficient macrophages also showed low STAT1 and STAT2 expression with defective response to virus. Thus, our studies uncovered the biological importance of HDAC3 on regulating antiviral immunity of macrophages through interaction with FOXK1 to regulate the expression of STAT1 and STAT2.
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Project description:Histone deacetylase 3 contributes to the anti-viral innate immunity of macrophages through interacting with FOXK1 to regulate STAT1 and STAT2
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Project description:Histone deacetylase 3 contributes to the anti-viral innate immunity of macrophages through interacting with FOXK1 to regulate STAT1/2 transcription [RNA-seq]
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Project description:Dengue virus (DENV) is a mosquito-borne flavivirus, and symptoms of infection range from asymptomatic to the severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). High viral loads correlate with disease severity, and both type I & II interferons (IFNs) are crucial for controlling viral replication. We have previously reported that signal transducer and activator of transcription (STAT) 1-deficient mice are resistant to DENV-induced disease, but little is known about this STAT1-independent mechanism of protection. To determine the molecular basis of the STAT1-independent pathway, mice lacking STAT1, STAT2, or both STAT1 and STAT2 were infected with a virulent mouse-adapted strain of DENV2. In the first 72 hours of infection, the single-deficient mice lacking STAT1 or STAT2 possessed 50-100 fold higher levels of viral RNA than wild type mice in the serum, spleen, and other visceral tissues, but remained resistant to DENV-induced death. In contrast, the double-deficient mice exhibited the early death phenotype previously observed in type I and II IFN receptor knockout mice (AG129), indicating that STAT2 is the mediator of the STAT1-independent host defense mechanism. Further studies demonstrated that this STAT2-dependent STAT1-independent mechanism requires the type I IFN receptor, and contributes to the autocrine amplification of type I IFN expression. Examination of gene expression in the spleen and bone marrow-derived macrophages following DENV infection revealed STAT2-dependent pathways can induce the transcription of a subset of interferon stimulated genes even in the absence of STAT1. Collectively, these results help elucidate the nature of the poorly understood STAT1-independent host defense mechanism against viruses by identifying a functional type I IFN/STAT2 signaling pathway following DENV infection in vivo.
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Project description:It is well known that IFNα/β activates the JAK/STAT signaling pathway and suppresses viral replication through induction of interferon stimulated genes (ISGs). Here we reported that knockout of HDAC3 from macrophages resulted in decreased expression of STAT1 and STAT2, leading to a defective anti-viral immunity in cells and mice. Further studies showed that HDAC3 interacted with a conserved transcription factor Forkhead Box K1 (FOXK1), co-localized with FOXK1 at the promoter of STAT1 and STAT2, and was required for protecting FOXK1 from lysosomal system mediated degradation. Constantly, FOXK1 deficient macrophages also showed low STAT1 and STAT2 expression with defective response to virus. Thus, our studies uncovered the biological importance of HDAC3 on regulating antiviral immunity of macrophages through interaction with FOXK1 to regulate the expression of STAT1 and STAT2.
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