Others The ASK family kinases differentially mediate type I interferon induction and apoptosis during the antiviral response

Okazaki, Tomohiko  ,  Higuchi, Maiko  ,  Takeda, Kohsuke  ,  Iwatsuki-Horimoto, Kiyoko  ,  Kiso, Maki  ,  Miyagishi, Makoto  ,  Yanai, Hideyuki  ,  Kato, Atsushi  ,  Yoneyama, Mitsutoshi  ,  Fujita, Takashi  ,  Taniguchi, Tadatsugu  ,  Kawaoka, Yoshihiro  ,  Ichijo, Hidenori  ,  Gotoh, Yukiko

8 ( 388 ) 2015-08-04 , American Association for the Advancement of Science , Laboratory of Molecular Biology, Graduate School of Pharmaceutical Sciences, The University of Tokyo , Division of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University , Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo , Molecular Composite Medicine Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) , Department of Molecular Immunology and Center for International Research on Integrative Biomedical Systems, Institute of Industrial Science, The University of Tokyo , Max Planck-The University of Tokyo Center for Integrative Inflammology , Department of Virology 3, National Institute of Infectious Diseases , Medical Mycology Research Center, Chiba University , Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University , Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo , ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency , Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison , Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo
ISSN:1945-0877 (print)1937-9145 (online)
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UTokyo Research "To be, or not to be: That is the question" URI: http://www.u-tokyo.ac.jp/en/utokyo-research/research-news/to-be-or-not-to-be-that-is-the-question.html
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.


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