title: Regulation of Retinoic Acid Inducible Gene-I (RIG-I) Activation by the Histone Deacetylase 6.
abstract: Retinoic acid inducible gene-I (RIG-I) is a cytosolic pathogen recognition receptor that initiates the immune response against many RNA viruses. Upon RNA ligand binding, RIG-I undergoes a conformational change facilitating its homo-oligomerization and activation that results in its translocation from the cytosol to intracellular membranes to bind its signaling adaptor protein, mitochondrial antiviral-signaling protein (MAVS). Here we show that RIG-I activation is regulated by reversible acetylation. Acetyl-mimetic mutants of RIG-I do not form virus-induced homo-oligomers, revealing that acetyl-lysine residues of the RIG-I repressor domain prevent assembly to active homo-oligomers. During acute infection, deacetylation of RIG-I promotes its oligomerization upon ligand binding. We identify histone deacetylase 6 (HDAC6) as the deacetylase that promotes RIG-I activation and innate antiviral immunity to recognize and restrict RNA virus infection.
authors.affiliation: Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, 750 Republican St, Seattle, WA, USA; Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, No. 1, Changde St, Taipei City, Taiwan. Electronic address: mliu@ntu.edu.tw.
authors.forename: Helene Minyi
authors.initials: HM
authors.lastname: Liu
authors.affiliation: Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA.
authors.forename: Fuguo
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, 750 Republican St, Seattle, WA, USA.
authors.forename: Yueh Ming
authors.initials: YM
authors.lastname: Loo
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, No. 1, Changde St, Taipei City, Taiwan.
authors.forename: ShuZhen
authors.initials: S
authors.lastname: Hsu
authors.affiliation: Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, 750 Republican St, Seattle, WA, USA.
authors.forename: Tien-Ying
authors.initials: TY
authors.lastname: Hsiang
authors.affiliation: Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Marcotrigiano
authors.affiliation: Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, 750 Republican St, Seattle, WA, USA. Electronic address: mgale@uw.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002019:Bufexamac / Q000494:pharmacology; D002460:Cell Line; D000071457:DEAD Box Protein 58 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D057809:HEK293 Cells; D016174:Hepacivirus / Q000235:genetics / Q000472:pathogenicity; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D015151:Immunoblotting; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D034741:RNA, Small Interfering; D002019:Bufexamac; D016899:Interferon-beta; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58
keywords: Deacetylation; HCV; HDAC6; Innate immunity; Interferon; RIG-I; West Nile virus