IRF2 transcriptionally induces GSDMD expression for pyroptosis

• Published in: Science signaling 2019-05, Vol.12 (582)
• Main Authors: Kayagaki, Nobuhiko, Lee, Bettina L, Stowe, Irma B, Kornfeld, Opher S, O'Rourke, Karen, Mirrashidi, Kathleen M, Haley, Benjamin, Watanabe, Colin, Roose-Girma, Merone, Modrusan, Zora, Kummerfeld, Sarah, Reja, Rohit, Zhang, Yafei, Cho, Vicky, Andrews, T Daniel, Morris, Lucy X, Goodnow, Christopher C, Bertram, Edward M, Dixit, Vishva M
• Format: Article
• Language: English
• Subjects: Apoptosis; Binding sites; Caspase; Caspase-1; Caspase-11; Caspase-4; Cell death; Disruption; Endothelial cells; Ethyl nitrosourea; Fever; Gene expression; Genetic screening; IL-1β; Inflammasomes; Inflammation; Interferon; Interferon regulatory factor; Interleukins; Macrophages; Medical treatment; Mice; Oligomerization; Plague; Pores; Proteins; Pyroptosis; Sepsis; Septic shock; Signaling; Therapeutic applications; Transcription activation; Transcription factors
• ISSN: 1945-0877; 1937-9145
• DOI: 10.1126/scisignal.aax4917

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