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IRF2 Transcriptionally Induces GSDMD 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-1beta (IL-1beta) 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-1beta 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.

Type Journal
ISBN 1937-9145 (Electronic) 1945-0877 (Linking)
Authors Kayagaki, N.; Lee, B. L.; Stowe, I. B.; Kornfeld, O. S.; O'Rourke, K.; Mirrashidi, K. M.; Haley, B.; Watanabe, C.; Roose-Girma, M.; Modrusan, Z.; Kummerfeld, S.; Reja, R.; Zhang, Y.; Cho, V.; Andrews, T. D.; Morris, L. X.; Goodnow, C. C.; Bertram, E. M.; Dixit, V. M.
Responsible Garvan Author Prof Christopher Goodnow
Publisher Name Science Signaling
Published Date 2019-05-21
Published Volume 12
Published Issue 582
Published Pages eaax4917
Status Always Electronic
DOI 10.1126/scisignal.aax4917
URL link to publisher's version