Pyroptosis is an inflammatory form of programmed cell death that plays important roles in immune protection against infections and in inflammatory disorders. Gasdermin D (GSDMD) is an executor of pyroptosis upon cleavage by caspases-1/4/5/11 following canonical and noncanonical inflammasome activation. GSDMD N-terminal domain assembles membrane pores to induce cytolysis, whereas its C-terminal domain inhibits cell death through intramolecular association with the N domain. The molecular mechanisms of autoinhibition for GSDMD are poorly characterized. Here we report the crystal structures of the human and murine GSDMD C-terminal domains, which differ from those of the full-length murine GSDMA3 and the human GSDMB C-terminal domain. Mutations of GSDMD C-domain residues predicted to locate at its interface with the N-domain enhanced pyroptosis. Our results suggest that GSDMDs may employ a distinct mode of intramolecular domain interaction and autoinhibition, which may be relevant to its unique role in pyroptosis downstream of inflammasome activation. The molecular mechanisms of autoinhibition for gasdermin D-mediated pyroptosis are poorly defined. Liu et al. report the crystal structures of the murine and human GSDMD C-terminal domains, which suggest that GSDMDs may employ a distinct mode of intramolecular domain interaction to regulate pyroptosis.
CITATION STYLE
Liu, Z., Wang, C., Rathkey, J. K., Yang, J., Dubyak, G. R., Abbott, D. W., & Xiao, T. S. (2018). Structures of the Gasdermin D C-Terminal Domains Reveal Mechanisms of Autoinhibition. Structure, 26(5), 778-784.e3. https://doi.org/10.1016/j.str.2018.03.002
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