title: Gcn5 and PCAF negatively regulate interferon-β production through HAT-independent inhibition of TBK1.
abstract: 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.
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA Department of Molecular Carcinogenesis, Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA.
authors.forename: Qihuang
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
authors.forename: Lenan
authors.initials: L
authors.lastname: Zhuang
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
authors.forename: Binbin
authors.initials: B
authors.lastname: Lai
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
authors.forename: Chaochen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Molecular Carcinogenesis, Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA.
authors.forename: Wenqian
authors.initials: W
authors.lastname: Li
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Dolan
authors.affiliation: Department of Molecular Carcinogenesis, Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
authors.forename: Keji
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Department of Physics, The George Washington University, Washington, DC, USA.
authors.forename: Weiqun
authors.initials: W
authors.lastname: Peng
authors.affiliation: Department of Molecular Carcinogenesis, Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA sroth@mdanderson.org kaig@niddk.nih.gov.
authors.forename: Sharon Y R
authors.initials: SY
authors.lastname: Dent
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA sroth@mdanderson.org kaig@niddk.nih.gov.
authors.forename: Kai
authors.initials: K
authors.lastname: Ge
mesh_terms: D000107:Acetylation; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D006657:Histones; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C403191:TBK1 protein, human
keywords: Gcn5/PCAF; H3K9ac; TBK1; innate immune signaling; interferon‐β