Research ArticleImmunology

IRF2 transcriptionally induces GSDMD expression for pyroptosis

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Science Signaling  21 May 2019:
Vol. 12, Issue 582, eaax4917
DOI: 10.1126/scisignal.aax4917

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IRF2 induces gasdermin D

In response to activation of canonical and noncanonical inflammasomes, a subset of caspases processes the protein gasdermin D (GSDMD) to release N-terminal fragments that oligomerize and form pores in the plasma membrane. Assembly of the GSDMD pore leads to release of the inflammatory cytokine IL-1β and causes cell death by pyroptosis. Kayagaki et al. found that loss of the transcriptional regulator IRF2 reduced GSDMD mRNA and protein abundance in mice and in human cells, resulting in decreased IL-1β secretion and reduced pyroptosis in response to inflammasome activation. Given that loss of GSDMD in mice results in ameliorated disease in models of inflammasome-driven pathologies, these findings suggest that IRF2 might be a therapeutic target for the treatment of sepsis and other inflammasome-mediated diseases.

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.

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