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

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  • Jie Yang
    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
  • Zhonghua Liu
    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
  • Chuanping Wang
    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
  • Rui Yang
    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
  • Joseph K. Rathkey
    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
  • Otis W. Pinkard
    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
  • Wuxian Shi
    Center for Proteomics and Bioinformatics, Center for Synchrotron Biosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
  • Yinghua Chen
    Protein Expression Purification Crystallization and Molecular Biophysics Core, Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
  • George R. Dubyak
    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
  • Derek W. Abbott
    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
  • Tsan Sam Xiao
    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;

抄録

<jats:title>Significance</jats:title> <jats:p> 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, <jats:italic>N</jats:italic> -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. </jats:p>

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