title: Mitochondrial damage elicits a TCDD-inducible poly(ADP-ribose) polymerase-mediated antiviral response.
abstract: The innate immune system senses RNA viruses by pattern recognition receptors (PRRs) and protects the host from virus infection. PRRs mediate the production of immune modulatory factors and direct the elimination of RNA viruses. Here, we show a unique PRR that mediates antiviral response. Tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP ribose) polymerase (TIPARP), a Cysteine3 Histidine (CCCH)-type zinc finger-containing protein, binds to Sindbis virus (SINV) RNA via its zinc finger domain and recruits an exosome to induce viral RNA degradation. TIPARP typically localizes in the nucleus, but it accumulates in the cytoplasm after SINV infection, allowing targeting of cytoplasmic SINV RNA. Redistribution of TIPARP is induced by reactive oxygen species (ROS)-dependent oxidization of the nuclear pore that affects cytoplasmic-nuclear transport. BCL2-associated X protein (BAX) and BCL2 antagonist/killer 1 (BAK1), B-cell leukemia/lymphoma 2 (BCL2) family members, mediate mitochondrial damage to generate ROS after SINV infection. Thus, TIPARP is a viral RNA-sensing PRR that mediates antiviral responses triggered by BAX- and BAK1-dependent mitochondrial damage.
authors.affiliation: Division of Inflammation Biology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan.|Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kozaki
authors.affiliation: Department of Clinical Laboratory, National Hospital Organization Nagoya Medical Center, Nakaku, Nagoya 460-0001, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Komano
authors.affiliation: Division of Virology, Department of Infectious Diseases, Osaka Prefectural Institute of Public Health, Higashinari-ku, Osaka 537-0025, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Kanbayashi
authors.affiliation: Division of Inflammation Biology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan.|Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Takahama
authors.affiliation: Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Misawa
authors.affiliation: Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Laboratory of Infection and Prevention, Institute for Frontier Life and Medical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.affiliation: Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Shigeomi
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Matsuura
authors.affiliation: Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; sakira@biken.osaka-u.ac.jp saitohtatsuya@tokushima-u.ac.jp.|Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Division of Inflammation Biology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan; sakira@biken.osaka-u.ac.jp saitohtatsuya@tokushima-u.ac.jp.|Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Saitoh
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000276:immunology; D003593:Cytoplasm / Q000235:genetics / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000473:pathology / Q000821:virology; D033703:Nucleoside Transport Proteins; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000276:immunology; D012328:RNA Viruses / Q000235:genetics* / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051192:Receptors, Pattern Recognition / Q000235:genetics* / Q000276:immunology; D012845:Sindbis Virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000276:immunology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000276:immunology
chemical_list: C494772:BAK1 protein, human; C494826:BAX protein, human; D033703:Nucleoside Transport Proteins; D017382:Reactive Oxygen Species; D051192:Receptors, Pattern Recognition; C579717:TiPARP protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D011065:Poly(ADP-ribose) Polymerases
keywords: RNA degradation; antiviral response; innate immunity; mitochondrial damage; reactive oxygen species