title: Constitutive aryl hydrocarbon receptor signaling constrains type I interferon-mediated antiviral innate defense.
abstract: Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxic activity of many environmental xenobiotics. However, its role in innate immune responses during viral infection is not fully understood. Here we demonstrate that constitutive AHR signaling negatively regulates the type I interferon (IFN-I) response during infection with various types of virus. Virus-induced IFN-β production was enhanced in AHR-deficient cells and mice and resulted in restricted viral replication. We found that AHR upregulates expression of the ADP-ribosylase TIPARP, which in turn causes downregulation of the IFN-I response. Mechanistically, TIPARP interacted with the kinase TBK1 and suppressed its activity by ADP-ribosylation. Thus, this study reveals the physiological importance of endogenous activation of AHR signaling in shaping the IFN-I-mediated innate response and, further, suggests that the AHR-TIPARP axis is a potential therapeutic target for enhancing antiviral responses.
authors.affiliation: Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Taisho
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.|Department of Gastroenterology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Horimoto
authors.affiliation: Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.|Molecular Medical Biochemistry Unit, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kameyama
authors.affiliation: Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.|Molecular Medical Biochemistry Unit, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Hayakawa
authors.affiliation: Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.|Department of Gastroenterology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamato
authors.affiliation: Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.|Department of Gastroenterology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Dazai
authors.affiliation: Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.|Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan.
authors.forename: Ayato
authors.initials: A
authors.lastname: Takada
authors.affiliation: Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan.|Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kida
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Debbie
authors.initials: D
authors.lastname: Bott
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Hutin
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tania H
authors.identifier: 0000-0001-7897-4890
authors.initials: TH
authors.lastname: Watts
authors.affiliation: Health Sciences University of Hokkaido, Toubetu, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Asaka
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.|Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Jason
authors.initials: J
authors.lastname: Matthews
authors.affiliation: Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.|Molecular Medical Biochemistry Unit, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Takaoka
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D014777:Virus Diseases / Q000276:immunology*; D014779:Virus Replication
chemical_list: D007370:Interferon Type I; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; C000594530:2,3,7,8-tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase, mouse; D011065:Poly(ADP-ribose) Polymerases