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Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death

Author

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  • Jianjin Shi

    (Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University
    National Institute of Biological Sciences)

  • Yue Zhao

    (National Institute of Biological Sciences)

  • Kun Wang

    (National Institute of Biological Sciences)

  • Xuyan Shi

    (National Institute of Biological Sciences)

  • Yue Wang

    (National Institute of Biological Sciences)

  • Huanwei Huang

    (National Institute of Biological Sciences)

  • Yinghua Zhuang

    (National Institute of Biological Sciences)

  • Tao Cai

    (National Institute of Biological Sciences)

  • Fengchao Wang

    (National Institute of Biological Sciences)

  • Feng Shao

    (National Institute of Biological Sciences
    National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
    National Institute of Biological Sciences, Beijing, Collaborative Innovation Center for Cancer Medicine)

Abstract

Inflammatory caspases (caspase-1, -4, -5 and -11) are critical for innate defences. Caspase-1 is activated by ligands of various canonical inflammasomes, and caspase-4, -5 and -11 directly recognize bacterial lipopolysaccharide, both of which trigger pyroptosis. Despite the crucial role in immunity and endotoxic shock, the mechanism for pyroptosis induction by inflammatory caspases is unknown. Here we identify gasdermin D (Gsdmd) by genome-wide clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 nuclease screens of caspase-11- and caspase-1-mediated pyroptosis in mouse bone marrow macrophages. GSDMD-deficient cells resisted the induction of pyroptosis by cytosolic lipopolysaccharide and known canonical inflammasome ligands. Interleukin-1β release was also diminished in Gsdmd−/− cells, despite intact processing by caspase-1. Caspase-1 and caspase-4/5/11 specifically cleaved the linker between the amino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains in GSDMD, which was required and sufficient for pyroptosis. The cleavage released the intramolecular inhibition on the gasdermin-N domain that showed intrinsic pyroptosis-inducing activity. Other gasdermin family members were not cleaved by inflammatory caspases but shared the autoinhibition; gain-of-function mutations in Gsdma3 that cause alopecia and skin defects disrupted the autoinhibition, allowing its gasdermin-N domain to trigger pyroptosis. These findings offer insight into inflammasome-mediated immunity/diseases and also change our understanding of pyroptosis and programmed necrosis.

Suggested Citation

  • Jianjin Shi & Yue Zhao & Kun Wang & Xuyan Shi & Yue Wang & Huanwei Huang & Yinghua Zhuang & Tao Cai & Fengchao Wang & Feng Shao, 2015. "Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death," Nature, Nature, vol. 526(7575), pages 660-665, October.
  • Handle: RePEc:nat:nature:v:526:y:2015:i:7575:d:10.1038_nature15514
    DOI: 10.1038/nature15514
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    Cited by:

    1. Yingqi Deng & Eleonore Ostermann & Wolfram Brune, 2024. "A cytomegalovirus inflammasome inhibitor reduces proinflammatory cytokine release and pyroptosis," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Keyla S. G. de Sá & Luana A. Amaral & Tamara S. Rodrigues & Adriene Y. Ishimoto & Warrison A. C. Andrade & Leticia Almeida & Felipe Freitas-Castro & Sabrina S. Batah & Sergio C. Oliveira & Mônica T. P, 2023. "Gasdermin-D activation promotes NLRP3 activation and host resistance to Leishmania infection," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Hanhan Ning & Shan Huang & Yang Lei & Renyong Zhi & Han Yan & Jiaxing Jin & Zhenyu Hu & Kaimin Guo & Jinhua Liu & Jie Yang & Zhe Liu & Yi Ba & Xin Gao & Deqing Hu, 2022. "Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    4. Chaiheon Lee & Mingyu Park & W. C. Bhashini Wijesinghe & Seungjin Na & Chae Gyu Lee & Eunhye Hwang & Gwangsu Yoon & Jeong Kyeong Lee & Deok-Ho Roh & Yoon Hee Kwon & Jihyeon Yang & Sebastian A. Hughes , 2024. "Oxidative photocatalysis on membranes triggers non-canonical pyroptosis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Zhu, Ligang & Li, Xiang & Xu, Fei & Yin, Zhiyong & Jin, Jun & Liu, Zhilong & Qi, Hong & Shuai, Jianwei, 2022. "Network modeling-based identification of the switching targets between pyroptosis and secondary pyroptosis," Chaos, Solitons & Fractals, Elsevier, vol. 155(C).
    6. Yuanyuan Wei & Beidi Lan & Tao Zheng & Lin Yang & Xiaoxia Zhang & Lele Cheng & Gulinigaer Tuerhongjiang & Zuyi Yuan & Yue Wu, 2023. "GSDME-mediated pyroptosis promotes the progression and associated inflammation of atherosclerosis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    7. Jin, Jun & Xu, Fei & Liu, Zhilong & Shuai, Jianwei & Li, Xiang, 2024. "Quantifying the underlying landscape, entropy production and biological path of the cell fate decision between apoptosis and pyroptosis," Chaos, Solitons & Fractals, Elsevier, vol. 178(C).
    8. Xionghui Ding & Hiroto Kambara & Rongxia Guo & Apurva Kanneganti & Maikel Acosta-Zaldívar & Jiajia Li & Fei Liu & Ting Bei & Wanjun Qi & Xuemei Xie & Wenli Han & Ningning Liu & Cunling Zhang & Xiaoyu , 2021. "Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    9. Yuan Lu & Wenbo He & Xin Huang & Yu He & Xiaojuan Gou & Xiaoke Liu & Zhe Hu & Weize Xu & Khaista Rahman & Shan Li & Sheng Hu & Jie Luo & Gang Cao, 2021. "Strategies to package recombinant Adeno-Associated Virus expressing the N-terminal gasdermin domain for tumor treatment," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    10. Stefania A. Mari & Kristyna Pluhackova & Joka Pipercevic & Matthew Leipner & Sebastian Hiller & Andreas Engel & Daniel J. Müller, 2022. "Gasdermin-A3 pore formation propagates along variable pathways," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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