Journal
SCIENCE SIGNALING
Volume 8, Issue 388, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aab1883
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Funding
- Ministry of Education, Culture, Sports and Technology (MEXT) of Japan
- Core Research for Evolutionary Science and Technology from the Japan Science and Technology Agency
- Japan Society for the Promotion of Science
- Global Centers of Excellence Program (Integrative Life Science Based on the Study of BiosignalingMechanisms), MEXT, Japan
- Grants-in-Aid for Scientific Research [15H05787, 15H05773, 15H02357, 15H02514, 26293016, 24115004, 22123003, 26114009] Funding Source: KAKEN
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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-beta (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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