Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death
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.
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Gsdmd−/− macrophages are resistant to LPS-induced and Gram-negative bacteria-induced pyroptosis.
“Gsdmd−/− macrophages are resistant to LPS-induced and Gram-negative bacteria-induced pyroptosis”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [626]
Gsdmd−/− mice survive doses of LPS that induce lethal endotoxic shock in wild-type counterparts.
“Gsdmd−/− mice survive doses of LPS that induce lethal endotoxic shock in their wild-type counterparts [621, 626].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [626]
Once activated beyond a specific threshold, inflammatory caspases precipitate pyroptosis by catalyzing proteolytic cleavage of GSDMD.
“Once activated beyond a specific threshold, inflammatory caspases precipitate pyroptosis by catalyzing the proteolytic cleavage of GSDMD [621, 626, 627].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [626]
The N-terminal domains of other gasdermin family members, including GSDMA, GSDMB, GSDMC, GSDME/DFNA5, and GSDMA3, resemble GSDMD as they display pore-forming and pyroptotic activity.
“the (shared) N-terminal domains of other members of the gasdermin family, including GSDMA, GSDMB, GSDMC, GSDME/DFNA5, and GSDMA3 (which is encoded by the mouse—but not the human—genome), resemble those of GSDMD as they display pore-forming and pyroptotic activity [39, 613, 626, 629].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [626]
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- Authors
- Shi, J., Zhao, Y., Wang, K., Shi, X., Wang, Y., Huang, H., Zhuang, Y., Cai, T., Wang, F., & Shao, F.
- Affiliations
- Peking University (CN)
- National Institute of Biological Sciences, Beijing (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Shao, Feng
- Venue
- Nature
- Published
- 2015-09-16
- Volume
- 526
- Issue
- 7575
- Pages
- 660-665
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1864325817
- Cited by
- 6,659
- References
- 32
- Citations by year
- 2026: 859 · 2025: 881 · 2024: 911 · 2023: 954 · 2022: 924 · 2021: 674 · 2020: 512 · 2019: 363 · 2018: 241 · 2017: 196 · 2016: 121 · 2015: 16 · 2013: 1 · 2012: 1
- FWCI
- 83.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- pyroptosis, gasdermin D, inflammatory caspases, caspase-1, caspase-11, caspase-4, caspase-5, autoinhibition, necroptosis, inflammasome, lipopolysaccharide, IL-1β, bone marrow-derived macrophages
- MeSH terms
- Gasdermins, Animals, Cell Line, Humans, Inflammation, Lipopolysaccharides, Macrophages, Male, Mice, Inbred C57BL, Necrosis, Neoplasm Proteins, Protein Processing, Post-Translational, Proteins, Substrate Specificity, Apoptosis, Protein Structure, Tertiary, Caspases, Caspase 1, Phosphate-Binding Proteins, Intracellular Signaling Peptides and Proteins, Apoptosis Regulatory Proteins, Mice, Interleukin-1beta, Inflammasomes, CRISPR-Cas Systems
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