title: Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity.
abstract: The DNA methyltransferase Dnmt3a has high expression in terminally differentiated macrophages; however, its role in innate immunity remains unknown. Here we report that deficiency in Dnmt3a selectively impaired the production of type I interferons triggered by pattern-recognition receptors (PRRs), but not that of the proinflammatory cytokines TNF and IL-6. Dnmt3a-deficient mice exhibited enhanced susceptibility to viral challenge. Dnmt3a did not directly regulate the transcription of genes encoding type I interferons; instead, it increased the production of type I interferons through an epigenetic mechanism by maintaining high expression of the histone deacetylase HDAC9. In turn, HDAC9 directly maintained the deacetylation status of the key PRR signaling molecule TBK1 and enhanced its kinase activity. Our data add mechanistic insight into the crosstalk between epigenetic modifications and post-translational modifications in the regulation of PRR signaling and activation of antiviral innate immune responses.
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.|National Key Laboratory of Medical Molecular Biology &Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: National Key Laboratory of Medical Molecular Biology &Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.|National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yiqi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Dezhi
authors.initials: D
authors.lastname: Zhao
authors.affiliation: National Key Laboratory of Medical Molecular Biology &Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Qicong
authors.initials: Q
authors.lastname: Shen
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Xingguang
authors.initials: X
authors.lastname: Liu
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Zhu
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Advanced Translational Medicine Institute, Tongji University, Shanghai, China.
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, California, USA.
authors.forename: Guoping
authors.identifier: 0000-0001-5235-6410
authors.initials: G
authors.lastname: Fan
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.|National Key Laboratory of Medical Molecular Biology &Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.|National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000107:Acetylation; D000818:Animals; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000067996:RAW 264.7 Cells; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D018353:Rhabdoviridae Infections / Q000276:immunology*; D015398:Signal Transduction; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology*
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D007370:Interferon Type I; D051192:Receptors, Pattern Recognition; D012097:Repressor Proteins; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C486545:Hdac9 protein, mouse; D006655:Histone Deacetylases