1. Academic Validation
  2. 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.
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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