PMID:26243192

Citation	Okazaki, T, Higuchi, M, Takeda, K, Iwatsuki-Horimoto, K, Kiso, M, Miyagishi, M, Yanai, H, Kato, A, Yoneyama, M, Fujita, T, Taniguchi, T, Kawaoka, Y, Ichijo, H and Gotoh, Y (2015) The ASK family kinases differentially mediate induction of type I interferon and apoptosis during the antiviral response. Sci Signal 8:ra78
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.
Links	PubMed Online version:10.1126/scisignal.aab1883
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:M3K5		GO:0002224: toll-like receptor signaling pathway	ECO:0000314:		P		Figure 3 and S6 show that M3K5 (reffered to here as ASK1) is required for activation of downstream TLR-dependent signaling proteins	complete CACAO 11202
HUMAN:M3K5		GO:0023014: signal transduction by protein phosphorylation	ECO:0000314:		P		Figure 4 shows repression of M3K5 (named here as ASK1) results in lower phosphorylation of downstream signaling molecules	complete CACAO 11213
HUMAN:MAVS		GO:0039529: RIG-I signaling pathway	ECO:0000314:		P		Figure 1. Inhibition of IPS-1(MAVS) resulted in lowered downstream activity of RIG-1 pathway.	complete CACAO 11190
HUMAN:MAVS		GO:0023014: signal transduction by protein phosphorylation	ECO:0000314:		P		Figure S1 shows that interference of MAVS (referred to here as IPS-1) causes loss of phosphorylation of downstream signaling molecules	complete CACAO 11210
HUMAN:IFIH1		GO:0023014: signal transduction by protein phosphorylation	ECO:0000314:		P		S1 shows that IFIH1(referred to here as MDA5) is required for phosporylation of downstream signaling proteins	complete CACAO 11212
HUMAN:IRF3		GO:0039529: RIG-I signaling pathway	ECO:0000314:		P		Figure S1 shows lack of IRF3 expression in strains where transcription of RLR pathway intermediates are interfered with (MDA5 and IPS-1)	complete CACAO 11204
HUMAN:IRF3		GO:0039530: MDA-5 signaling pathway	ECO:0000314:		P		Figure S1 shows lack of IRF3 expression when MDA5 expression is inhibited	complete CACAO 11205

References

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