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Mechanism of gasdermin D recognition by inflammatory caspases and their inhibition by a gasdermin D-derived peptide inhibitor [Immunology and Inflammation]

The inflammasomes are signaling platforms that promote the activation of inflammatory caspases such as caspases-1, -4, -5, and -11, which cleave gasdermin D (GSDMD) to induce pyroptotic cell death. The mechanisms of GSDMD recognition by inflammatory caspases remain poorly understood. Here, we demonstrate that the catalytic domains of inflammatory caspases can directly bind to GSDMD or its cleavage site peptide, FLTD. A GSDMD-derived inhibitor, N -acetyl-Phe-Leu-Thr-Asp-chloromethylketone (Ac-FLTD-CMK), inhibits GSDMD cleavage in vitro and suppresses pyroptosis downstream of both canonical and noncanonical inflammasomes. By contrast, the inhibitor does not target caspase-3 or apoptosis, suggesting that it is specific for inflammatory caspases. Structure of caspase-1 in complex with Ac-FLTD-CMK reveals extensive enzyme–inhibitor interactions that shed light on GSDMD recognition by inflammatory caspases.

Authors:   Jie Yang; Zhonghua Liu; Chuanping Wang; Rui Yang; Joseph K. Rathkey; Otis W. Pinkard; Wuxian Shi; Yinghua Chen; George R. Dubyak; Derek W. Abbott; Tsan Sam Xiao
Journal:   Proceedings of the National Academy of Sciences current issue
Volume:   115
edition:   26
Year:   2018
Pages:   6792
DOI:   10.1073/pnas.1800562115
Publication date:   26-Jun-2018
Facts, background information, dossiers
  • inflammasomes
  • Cleavage
More about Proceedings of the National Academy of Sciences
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