Journal Article 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 )  , p.ra78 , 2015-08-04 , American Association for the Advancement of Science
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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