Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death

Jianjin Shi, Yue Zhao, Kun Wang, Xuyan Shi, Yue Wang, Huanwei Huang, Yinghua Zhuang, Tao Cai, Fengchao Wang and Feng Shao ()
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Jianjin Shi: Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University
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

Nature, 2015, vol. 526, issue 7575, 660-665

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature15514

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