IRF2 transcriptionally induces <i>GSDMD</i> expression for pyroptosis

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.