Publication Date:
2019
Description:
〈p〉Gasdermin-D (GSDMD) is cleaved by caspase-1, caspase-4, and caspase-11 in response to canonical and noncanonical inflammasome activation. Upon cleavage, GSDMD oligomerizes and forms plasma membrane pores, resulting in interleukin-1β (IL-1β) secretion, pyroptotic cell death, and inflammatory pathologies, including periodic fever syndromes and septic shock—a plague on modern medicine. Here, we showed that IRF2, a member of the interferon regulatory factor (IRF) family of transcription factors, was essential for the transcriptional activation of 〈i〉GSDMD.〈/i〉 A forward genetic screen with 〈i〉N〈/i〉-ethyl-〈i〉N〈/i〉-nitrosourea (ENU)–mutagenized mice linked IRF2 to inflammasome signaling. 〈i〉GSDMD〈/i〉 expression was substantially attenuated in 〈i〉IRF2-〈/i〉deficient macrophages, endothelial cells, and multiple tissues, which corresponded with reduced IL-1β secretion and inhibited pyroptosis. Mechanistically, IRF2 bound to a previously uncharacterized but unique site within the 〈i〉GSDMD〈/i〉 promoter to directly drive 〈i〉GSDMD〈/i〉 transcription for the execution of pyroptosis. Disruption of this single IRF2-binding site abolished signaling by both the canonical and noncanonical inflammasomes. Together, our data illuminate a key transcriptional mechanism for expression of the gene encoding GSDMD, a critical mediator of inflammatory pathologies.〈/p〉
Print ISSN:
1945-0877
Electronic ISSN:
1937-9145
Topics:
Biology
,
Medicine
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