Gcn5 and PCAF negatively regulate interferon β production through HAT-independent inhibition of TBK1
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE60969 | GEO | 2014/09/03
SECONDARY ACCESSION(S): PRJNA260002
REPOSITORIES: GEO
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Project description:Viral infection triggers innate immune signaling, which in turn induces interferon-β (IFN-β) production to establish innate antiviral immunity. Previous studies showed that Gcn5 (Kat2a), a histone acetyltransferase (HAT) with partial functional redundancy with PCAF (Kat2b), and Gcn5/PCAF-mediated histone H3K9 acetylation (H3K9ac) are enriched on the active IFNB gene promoter. However, whether Gcn5/PCAF and H3K9ac regulate IFN-β production is unknown. Here, we show that Gcn5/PCAF-mediated H3K9ac correlates well with, but is surprisingly dispensable for, the expression of endogenous IFNB and the vast majority of active genes in fibroblasts. Instead, Gcn5/PCAF repress IFN-β production and innate antiviral immunity in several cell types in a HAT-independent and non-transcriptional manner: by inhibiting the innate immune signaling kinase TBK1 in the cytoplasm. Our results thus identify Gcn5 and PCAF as negative regulators of IFN-β production and innate immune signaling.
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-09-03 | E-GEOD-60969 | biostudies-arrayexpress
Project description:Gcn5/PCAF double knockout (dKO) leads to loss of the global H3K9ac. RNA-Seq was performed to define the changes of gene expression in response to Gcn5/PCAF deletion and H3K9ac loss PCAF-/-;Gcn5f/D MEFs were infected with retroviral Cre to delete Gcn5 to generate Gcn5/PCAF dKO cells, followed by RNA-Seq analysis using spike-in RNA as controls
2014-09-03 | E-GEOD-60968 | biostudies-arrayexpress
Project description:Gcn5/PCAF dobule knockout (dKO) in MEFs leads to loss of the global H3K9ac, but only affect expression of a small nubmer of genes according to RNA-Seq data. To examine the function of H3K9ac on gene activation, H3K9ac ChIP-Seq was performed. We found that H3K9ac at Transcriptional Start sites (TSSs) of no-changed, up-regulated and down-regulated genes are all dramatially decreased in Gcn5/PCAF dKO cells, suggesting that H3K9ac is largely not required for gene activation. PCAF-/-;Gcn5f/D MEFs were infected with retroviral Cre to delete Gcn5 to generate Gcn5/PCAF dKO cells, followed by H3K9ac ChIP-Seq analysis
2014-09-03 | E-GEOD-60967 | biostudies-arrayexpress
Project description:Gcn5/PCAF double knockout (dKO) leads to loss of the global H3K9ac. RNA-Seq was performed to define the changes of gene expression in response to Gcn5/PCAF deletion and H3K9ac loss
2014-09-03 | GSE60968 | GEO
Project description:Gcn5/PCAF dobule knockout (dKO) in MEFs leads to loss of the global H3K9ac, but only affect expression of a small nubmer of genes according to RNA-Seq data. To examine the function of H3K9ac on gene activation, H3K9ac ChIP-Seq was performed. We found that H3K9ac at Transcriptional Start sites (TSSs) of no-changed, up-regulated and down-regulated genes are all dramatially decreased in Gcn5/PCAF dKO cells, suggesting that H3K9ac is largely not required for gene activation.
2014-09-03 | GSE60967 | GEO
Project description:The acetyltransferase Gcn5 is critical for embryogenesis and shows partial functional redundancy with its homolog PCAF. However, the tissue- and cell lineage-specific functions of Gcn5 and PCAF are still not well defined. Here we probe the functions of Gcn5 and PCAF in adipogenesis. We found that the double knockout (DKO) of Gcn5/PCAF inhibits expression of the master adipogenic transcription factor gene PPAR?, thereby preventing adipocyte differentiation. The adipogenesis defects in Gcn5/PCAF DKO cells are rescued by ectopic expression of peroxisome proliferator-activated receptor ? (PPAR?), suggesting Gcn5/PCAF act upstream of PPAR? to facilitate adipogenesis. The requirement of Gcn5/PCAF for PPAR? expression was unexpectedly bypassed by prolonged treatment with an adipogenic inducer, 3-isobutyl-1-methylxanthine (IBMX). However, neither PPAR? ectopic expression nor prolonged IBMX treatment rescued defects in Prdm16 expression in DKO cells, indicating that Gcn5/PCAF are essential for normal Prdm16 expression. Gcn5/PCAF regulate PPAR? and Prdm16 expression at different steps in the transcription process, facilitating RNA polymerase II recruitment to Prdm16 and elongation of PPAR? transcripts. Overall, our study reveals that Gcn5/PCAF facilitate adipogenesis through regulation of PPAR? expression and regulate brown adipogenesis by influencing Prdm16 expression.
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Project description:TANK-binding kinase 1 (TBK1) is an important serine/threonine-protein kinase that mediates phosphorylation and nuclear translocation of IRF3, which contributes to induction of type I interferons (IFNs) in the innate antiviral response. In mammals, TBK1 spliced isoform negatively regulates the virus-triggered IFN-? signaling pathway by disrupting the interaction between retinoic acid-inducible gene I (RIG-I) and mitochondria antiviral-signaling protein (MAVS). However, it is still unclear whether alternative splicing patterns and the function of TBK1 isoform(s) exist in teleost fish. In this study, we identify two alternatively spliced isoforms of TBK1 from zebrafish, termed TBK1_tv1 and TBK1_tv2. Both TBK1_tv1 and TBK1_tv2 contain an incomplete STKc_TBK1 domain. Moreover, the UBL_TBK1_like domain is also missing for TBK1_tv2. TBK1_tv1 and TBK1_tv2 are expressed in zebrafish larvae. Overexpression of TBK1_tv1 and TBK1_tv2 inhibits RIG-I-, MAVS-, TBK1-, and IRF3-mediated activation of IFN promoters in response to spring viremia of carp virus infection. Also, TBK1_tv1 and TBK1_tv2 inhibit expression of IFNs and IFN-stimulated genes induced by MAVS and TBK1. Mechanistically, TBK1_tv1 and TBK1_tv2 competitively associate with TBK1 and IRF3 to disrupt the formation of a functional TBK1-IRF3 complex, impeding the phosphorylation of IRF3 mediated by TBK1. Collectively, these results demonstrate that TBK1 spliced isoforms are dominant negative regulators in the RIG-I/MAVS/TBK1/IRF3 antiviral pathway by targeting the functional TBK1-IRF3 complex formation. Identification and functional characterization of piscine TBK1 spliced isoforms may contribute to understanding the role of TBK1 expression in innate antiviral response.
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Project description:BACKGROUND:Coronaviruses such as severe acute respiratory syndrome (SARS) coronavirus (SCoV) and mouse hepatitis virus A59 (MHV-A59) have evolved strategies to disable the innate immune system for productive replication and spread of infection. We have previously shown that papain-like protease domain 2 (PLP2), a catalytic domain of the nonstructural protein 3 (nsp3) of MHV-A59, encodes a deubiquitinase (DUB) and inactivates IFN regulatory factor 3 (IRF3) thereby the type I interferon (IFN) response. PRINCIPAL FINDINGS:Here we provide further evidence that PLP2 may also target TANK-binding kinase-1 (TBK1), the upstream kinase of IRF3 in the IFN signaling pathway. Overexpression experiments showed that PLP2 deubiquitinated TBK1 and reduced its kinase activity, hence inhibited IFN-? reporter activity. Albeit promiscuous in deubiquitinating cellular proteins, PLP2 inactivated TBK1 and IFN-? response in TNF receptor associated factor 3 (TRAF3) deficient cells, suggesting that targeting TBK1 would be sufficient for PLP2 to inhibit IRF3 activation. This notion was further supported by in vitro kinase assays, in which prior treatment of TBK1 with PLP2 inhibited its kinase activity to phosphorylate IRF3. Intriguing enough, results of PLP2 overexpression system and MHV-A59 infection system proved that PLP2 formed an inactive complex with TBK1 and IRF3 in the cytoplasm and the presence of PLP2 stabilized the hypo-phosphorylated IRF3-TBK1 complex in a dose-dependent manner. CONCLUSIONS:These results suggest that PLP2 not only inactivates TBK1, but also prevents IRF3 nuclear translocation hence inhibits IFN transcription activation. Identification of the conserved DUB activity of PLP2 in suppression of IFN signaling would provide a useful clue to the development of therapeutics against coronaviruses infection.
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Project description:Estrogen-related receptor ? (ERR?) is a member of the nuclear receptor superfamily controlling energy homeostasis; however, its precise role in regulating antiviral innate immunity remains to be clarified. Here, we showed that ERR? deficiency conferred resistance to viral infection both in vivo and in vitro. Mechanistically, ERR? inhibited the production of type-I interferon (IFN-I) and the expression of multiple interferon-stimulated genes (ISGs). Furthermore, we found that viral infection induced TBK1-dependent ERR? stabilization, which in turn associated with TBK1 and IRF3 to impede the formation of TBK1-IRF3, IRF3 phosphorylation, IRF3 dimerization, and the DNA binding affinity of IRF3. The effect of ERR? on IFN-I production was independent of its transcriptional activity and PCG-1?. Notably, ERR? chemical inhibitor XCT790 has broad antiviral potency. This work not only identifies ERR? as a critical negative regulator of antiviral signaling, but also provides a potential target for future antiviral therapy.
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