Gasdermin-D (GSDMD) is cleaved by caspase-1/4/11 in response to canonical and non-canonical inflammasome activation. Upon cleavage,;	GSDMD oligomerizes and forms membrane pores, resulting in IL-1 secretion, pyroptotic cell death and inflammatory pathologies including periodic;	fever syndromes and septic shock  a plague on modern medicine. The transcriptional machinery that drives the expression of GSDMD is unknown.;	Here we show that IRF2, a member of the interferon-regulatory factor (IRF) family, is essential for the transcriptional activation of GSDMD.;	A forward genetic screen with ethyl-N-nitrosourea (ENU)-mutagenized mice unequivocally linked IRF2 to inflammasome signaling. Indeed,;	GSDMD transcript levels were highly attenuated in Irf2/ macrophages upon Irf2 deficiency in macrophages, endothelial cells, and multiple organs,;	corresponding to attenuated IL-1 secretion and inhibited pyroptosis. Mechanistically, IRF2 binds a previously uncharacterized site within the GSDMD;	promoter to directly drive GSDMD transcription for execution of pyroptosis in response to canonical and non-canonical inflammasome activation.;	Our data illuminate a prominent transcriptional mechanism for the expression of GSDMD, a key mediator of inflammatory pathologies. SOURCE: Rohit Reja (rejar@gene.com) -  Genentech

Pluto Bioinformatics

GSE130195: Differences in gene expression between WT and IRF2 KO cells