title: Virus infection triggers SUMOylation of IRF3 and IRF7, leading to the negative regulation of type I interferon gene expression.
abstract: Viral infection activates Toll-like receptor and RIG-I (retinoic acid-inducible gene I) signaling pathways, leading to phosphorylation of IRF3 (interferon regulatory factor 3) and IRF7 and stimulation of type I interferon (IFN) transcription, a process important for innate immunity. We show that upon vesicular stomatitis virus infection, IRF3 and IRF7 are modified not only by phosphorylation but by the small ubiquitin-related modifiers SUMO1, SUMO2, and SUMO3. SUMOylation of IRF3 and IRF7 was dependent on the activation of Toll-like receptor and RIG-I pathways but not on the IFN-stimulated pathway. However, SUMOylation of IRF3 and IRF7 was not dependent on their phosphorylation, and vice versa. We identified Lys(152) of IRF3 and Lys(406) of IRF7 to be their sole small ubiquitin-related modifier (SUMO) conjugation site. IRF3 and IRF7 mutants defective in SUMOylation led to higher levels of IFN mRNA induction after viral infection, relative to the wild type IRFs, indicating a negative role for SUMOylation in IFN transcription. Together, SUMO modification is an integral part of IRF3 and IRF7 activity that contributes to postactivation attenuation of IFN production.
authors.affiliation: Department of Virology III, 208-0011, Japan. Electronic address: kubota@nih.go.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Department of Bacterial Pathogenesis and Infection Control, National Institute of Infectious Diseases Tokyo, 208-0011, Japan and the.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Matsuoka
authors.affiliation: Laboratory of Molecular Growth Regulation, Genomics of Differentiation Program, NICHD, National Institutes of Health, Bethesda, Maryland 20892-2753.
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Chang
authors.affiliation: Laboratory of Molecular Growth Regulation, Genomics of Differentiation Program, NICHD, National Institutes of Health, Bethesda, Maryland 20892-2753.
authors.forename: Prafullakumar
authors.initials: P
authors.lastname: Tailor
authors.affiliation: Department of Bacterial Pathogenesis and Infection Control, National Institute of Infectious Diseases Tokyo, 208-0011, Japan and the.
authors.forename: Tsuguo
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Virology III, 208-0011, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Tashiro
authors.affiliation: Department of Virology III, 208-0011, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.affiliation: Laboratory of Molecular Growth Regulation, Genomics of Differentiation Program, NICHD, National Institutes of Health, Bethesda, Maryland 20892-2753.
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism*; D007370:Interferon Type I / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D041681:NIH 3T3 Cells; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D014777:Virus Diseases / Q000378:metabolism*
chemical_list: C494232:IRF3 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D008565:Membrane Proteins; C437968:PLAAT4 protein, human; C452562:RARRES1 protein, human; D018168:Receptors, Retinoic Acid; D051193:Toll-Like Receptors; D008239:Lysine