2. Academic Validation
  3. Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis

Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis

  • Cell. 2020 Mar 5;180(5):941-955.e20. doi: 10.1016/j.cell.2020.02.002.
Kun Wang 1,  Qi Sun 2,  Xiu Zhong 1,  Mengxue Zeng 3,  Huan Zeng 4,  Xuyan Shi 3,  Zilin Li 2,  Yupeng Wang 2,  Qiang Zhao 5,  Feng Shao 6,  Jingjin Ding 7
Affiliations

Affiliations

  • 1 Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, National Institute of Biological Sciences, 102206 Beijing, China; National Institute of Biological Sciences, Beijing, 102206 Beijing, China.
  • 2 Research Unit of Pyroptosis and Immunity, Chinese Academy of Medical Sciences 2019RU076, 102206 Beijing, China; National Institute of Biological Sciences, Beijing, 102206 Beijing, China.
  • 3 National Institute of Biological Sciences, Beijing, 102206 Beijing, China.
  • 4 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China; National Institute of Biological Sciences, Beijing, 102206 Beijing, China.
  • 5 Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, China.
  • 6 Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, National Institute of Biological Sciences, 102206 Beijing, China; Research Unit of Pyroptosis and Immunity, Chinese Academy of Medical Sciences 2019RU076, 102206 Beijing, China; National Institute of Biological Sciences, Beijing, 102206 Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, 102206 Beijing, China. Electronic address: shaofeng@nibs.ac.cn.
  • 7 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China; National Institute of Biological Sciences, Beijing, 102206 Beijing, China. Electronic address: jding@ibp.ac.cn.
PMID: 32109412 DOI: 10.1016/j.cell.2020.02.002
Abstract

The Pyroptosis execution protein GSDMD is cleaved by inflammasome-activated Caspase-1 and LPS-activated caspase-11/4/5. The cleavage unmasks the pore-forming domain from GSDMD-C-terminal domain. How the caspases recognize GSDMD and its connection with Caspase activation are unknown. Here, we show site-specific caspase-4/11 autoprocessing, generating a p10 product, is required and sufficient for cleaving GSDMD and inducing Pyroptosis. The p10-form autoprocessed caspase-4/11 binds the GSDMD-C domain with a high affinity. Structural comparison of autoprocessed and unprocessed capase-11 identifies a β sheet induced by the autoprocessing. In caspase-4/11-GSDMD-C complex crystal structures, the β sheet organizes a hydrophobic GSDMD-binding interface that is only possible for p10-form caspase-4/11. The binding promotes dimerization-mediated Caspase activation, rendering a cleavage independently of the cleavage-site tetrapeptide sequence. Crystal structure of caspase-1-GSDMD-C complex shows a similar GSDMD-recognition mode. Our study reveals an unprecedented substrate-targeting mechanism for caspases. The hydrophobic interface suggests an additional space for developing inhibitors specific for pyroptotic caspases.

Keywords

caspase; caspase-1; caspase-11; cell death; gasdermin; inflammasome; innate immunity; lipopolysaccharide; pore-forming protein; pyroptosis.

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