title: The ASK family kinases differentially mediate induction of type I interferon and apoptosis during the antiviral response.
abstract: Viral infection activates host defense mechanisms, including the production of type I interferon (IFN) and the apoptosis of infected cells. We investigated whether these two antiviral responses were differentially regulated in infected cells. We showed that the mitogen-activated protein kinase (MAPK) kinase kinase (MAPKKK) apoptosis signal-regulating kinase 1 (ASK1) was activated in cells by the synthetic double-stranded RNA analog polyinosinic:polycytidylic acid [poly(I:C)] and by RNA viruses, and that ASK1 played an essential role in both the induction of the gene encoding IFN-β (IFNB) and apoptotic cell death. In contrast, we found that the MAPKKK ASK2, a modulator of ASK1 signaling, was essential for ASK1-dependent apoptosis, but not for inducing IFNB expression. Furthermore, genetic deletion of either ASK1 or ASK2 in mice promoted the replication of influenza A virus in the lung. These results indicated that ASK1 and ASK2 are components of the antiviral defense mechanism and suggested that ASK2 acts as a key modulator that promotes apoptosis rather than the type I IFN response. Because ASK2 is selectively present in epithelium-rich tissues, such as the lung, ASK2-dependent apoptosis may contribute to an antiviral defense in tissues with a rapid repair rate in which cells could be readily replaced.
authors.affiliation: Laboratory of Molecular Biology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan. tokazaki@mol.f.u-tokyo.ac.jp.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Okazaki
authors.affiliation: Laboratory of Molecular Biology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Higuchi
authors.affiliation: Division of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Iwatsuki-Horimoto
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Kiso
authors.affiliation: Molecular Composite Medicine Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba 305-8566, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyagishi
authors.affiliation: Department of Molecular Immunology and Center for International Research on Integrative Biomedical Systems, Institute of Industrial Science, The University of Tokyo, Tokyo 153-8505, Japan. Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo 153-8505, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yanai
authors.affiliation: Department of Quality Assurance and Radiological Protection, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.affiliation: Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Yoneyama
authors.affiliation: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Department of Molecular Immunology and Center for International Research on Integrative Biomedical Systems, Institute of Industrial Science, The University of Tokyo, Tokyo 153-8505, Japan. Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo 153-8505, Japan.
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan. Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53711, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.affiliation: Laboratory of Molecular Biology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Gotoh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D002478:Cells, Cultured; D004285:Dogs; D057809:HEK293 Cells; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D016899:Interferon-beta / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000821:virology; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics* / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008957:Models, Genetic; D011070:Poly I-C / Q000235:genetics; D034622:RNA Interference; D012327:RNA Virus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D012328:RNA Viruses / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D016019:Survival Analysis
chemical_list: D016899:Interferon-beta; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C116394:MAP kinase kinase kinase 6; D011070:Poly I-C