Pore-forming activity and structural autoinhibition of the gasdermin family
Abstract
Inflammatory caspases cleave the gasdermin D (GSDMD) protein to trigger pyroptosis, a lytic form of cell death that is crucial for immune defences and diseases. GSDMD contains a functionally important gasdermin-N domain that is shared in the gasdermin family. The functional mechanism of action of gasdermin proteins is unknown. Here we show that the gasdermin-N domains of the gasdermin proteins GSDMD, GSDMA3 and GSDMA can bind membrane lipids, phosphoinositides and cardiolipin, and exhibit membrane-disrupting cytotoxicity in mammalian cells and artificially transformed bacteria. Gasdermin-N moved to the plasma membrane during pyroptosis. Purified gasdermin-N efficiently lysed phosphoinositide/cardiolipin-containing liposomes and formed pores on membranes made of artificial or natural phospholipid mixtures. Most gasdermin pores had an inner diameter of 10–14 nm and contained 16 symmetric protomers. The crystal structure of GSDMA3 showed an autoinhibited two-domain architecture that is conserved in the gasdermin family. Structure-guided mutagenesis demonstrated that the liposome-leakage and pore-forming activities of the gasdermin-N domain are required for pyroptosis. These findings reveal the mechanism for pyroptosis and provide insights into the roles of the gasdermin family in necrosis, immunity and diseases.
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Membrane targeting enables GSDMD-N oligomerization, generating a pore responsible for rapid plasma membrane permeabilization.
“Membrane targeting enables GSDMD-N oligomerization, generating a pore that is responsible for rapid plasma membrane permeabilization [629–633].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [629]
On pyroptosis induction, inflammatory caspases relieve GSDMD auto-inhibition by cleaving the interdomain loop, promoting release of GSDMD-N.
“On pyroptosis induction, inflammatory caspases relieve this inhibition by catalyzing the proteolytic cleavage of the interdomain loop, which promotes the release of the pyroptotic inducer GSDMD-N [621, 629].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [629]
Cleaved GSDMD-N translocates to the inner leaflet of the plasma membrane or bacterial plasma membrane, where it binds with high specificity to selected phosphoinositides or cardiolipin.
“Cleaved GSDMD-N acquires the ability to translocate to the inner leaflet of the plasma membrane (or the bacterial plasma membrane), where it binds with high specificity to selected phosphoinositides (or cardiolipin) [629, 630].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [629]
The GSDMD pore consists of 16 symmetric protomers with an inner diameter of ~10-14 nm.
“the GSDMD pore has recently been characterized at the ultrastructural level, consisting of 16 symmetric protomers with an inner diameter of ~10–14 nm [629].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [629]
GSDMD is constitutionally auto-inhibited by binding of its C-terminal repressor domain to its N-terminal pore-forming domain.
“GSDMD is constitutionally auto-inhibited by the binding of its C-terminal repressor domain (GSDMD-C, or RD) to its N-terminal pore-forming domain (GSDMD-N, or PFD).”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [629]
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 [629]
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Pollock, N. M., Fernandes, J. P., Woodfield, J., Moussa, E., Hlavay, B., Branton, W. G., Wuest, M., Mohammadzadeh, N., Schmitt, L., Plemel, J. R., et al. (2024) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2023.10.022 · Cited by 21 · see citing works
Su, W., Xie, Z., Bai, X., Li, Z., & Liu, X. (2023) · Brain Sciences · doi:10.3390/brainsci13030478 · Cited by 7 · see citing works
- Authors
- Ding, J., Wang, K., Liu, W., She, Y., Sun, Q., Shi, J., Sun, H., Wang, D.-C., & Shao, F.
- Affiliations
- Chinese Academy of Sciences (CN)
- National Institute of Biological Sciences, Beijing (CN)
- Corresponding author
- Shao, Feng
- Venue
- Nature
- Published
- 2016-06-08
- Volume
- 535
- Issue
- 7610
- Pages
- 111-116
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2418806051
- Cited by
- 2,771
- References
- 44
- Citations by year
- 2026: 246 · 2025: 317 · 2024: 382 · 2023: 409 · 2022: 435 · 2021: 349 · 2020: 203 · 2019: 172 · 2018: 116 · 2017: 103 · 2016: 34
- FWCI
- 73.82
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-10-05)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- gasdermin, gasdermin D, GSDMA, pyroptosis, pore formation, autoinhibition, phosphoinositides, cardiolipin, membrane lipids, oligomerization, crystal structure, caspase cleavage, programmed cell death, innate immunity
- MeSH terms
- Pyroptosis, Gasdermins, Animals, Cardiolipins, Cell Line, Cell Membrane, Cell Membrane Permeability, DNA-Binding Proteins, Humans, Liposomes, Membrane Lipids, Models, Molecular, Necrosis, Neoplasm Proteins, Phosphatidylinositols, Proteins, Biomarkers, Tumor, Porosity, Protein Structure, Tertiary, Crystallography, X-Ray, Caspases, Phosphate-Binding Proteins, Intracellular Signaling Peptides and Proteins, Mice
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