Research ArticleImmunology

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

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Science Signaling  04 Aug 2015:
Vol. 8, Issue 388, pp. ra78
DOI: 10.1126/scisignal.aab1883

Viruses ASK for it

When a host cell is infected by a virus, cytosolic RIG-I–like receptors (RLRs) sense double-stranded RNA and stimulate the production of type I interferons (IFNs) to activate the immune response and also stimulate programmed cell death (apoptosis) to limit viral spread. Okazaki et al. found that in epithelial cells, the kinase ASK1 mediated RLR-dependent signaling in response to viral infection to activate the downstream kinases JNK and p38, resulting in both IFN production and apoptosis. However, experiments with influenza virus–infected mice showed that the related kinase ASK2 was required for ASK1-dependent apoptosis, but not IFN production. Together, these data suggest that the relative abundance of ASK1 and ASK2 determines the type of response that is elicited by viral infection.


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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