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.

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