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-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.
Source: Signal Transduction Knowledge Environment - Category: Science 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., Tags: STKE Research Articles Source Type: news