IRF2 transcriptionally induces GSDMD expression for pyroptosis

Abstract

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 GSDMD. A forward genetic screen with N-ethyl-N-nitrosourea (ENU)–mutagenized mice linked IRF2 to inflammasome signaling. GSDMD expression was substantially attenuated in IRF2-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 GSDMD promoter to directly drive GSDMD 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.

IRF 1 and IRF 2 regulate the non‐canonical inflammasome

“…In mouse macrophages, IRF2 induced the expression of gasdermin D but not caspase‐11, which is inducibly expressed in response to type I IFN . Macrophages from Irf2 −/− mice exhibited defective responses to canonical and non‐canonical inflammasome stimuli, comparable to Gsdmd −/− cells . Again through ChIP‐Seq analysis, an IRF2 binding motif was identified in the Gsdmd promoter, and was essential for expression in macrophages.…”

Inflammasome‐associated cell death: Pyroptosis, apoptosis, and physiological implications

“…A previous study suggested that interferon regulatory factor (IRF) 2 and IRF1 are transcription factors involved in the expression of GSDMD in murine macrophages and EA.hy926 cells, a human endothelial cell line, whereas another study found that IRF2 and IRF1 were required for the expression of caspase-4, but not GSDMD, in human macrophages (Figure 4). 79,80 Thus, IRF2 and IRF1 appear to regulate GSDMD expression in a species-and/or cell type-specific manner. Further studies are needed to clarify whether the expression of GSDMD in different tissues and cell types is regulated by IRF2 and IRF1 and/ or other transcription factors, epigenetic regulation, and cis-elements, and also whether no or the weak expression of GSDMD in certain cell types, such as neurons and mast cells that undergo apoptosis upon inflammasome formation, is important for limiting inflammasomeassociated inflammation and pathology by preventing pyroptosis.…”

Gasdermins and their role in immunity and inflammation

“…GSDMD is expressed in a wide range of tissues and cell types and is regulated by the transcription factor IRF2 (Kayagaki et al, 2019). It is highly expressed in gut epithelial cells, and both caspase-1 and -11 have previously been shown to play an important role in controlling intestinal pathogens (Saeki et al, 2000; Saeki and Sasaki, 2012; Knodler et al, 2014; Sellin et al, 2014).…”