GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death
Open accessAbstract
Pyroptosis is a lytic type of cell death that is initiated by inflammatory caspases. These caspases are activated within multi-protein inflammasome complexes that assemble in response to pathogens and endogenous danger signals. Pyroptotic cell death has been proposed to proceed via the formation of a plasma membrane pore, but the underlying molecular mechanism has remained unclear. Recently, gasdermin D (GSDMD), a member of the ill-characterized gasdermin protein family, was identified as a caspase substrate and an essential mediator of pyroptosis. GSDMD is thus a candidate for pyroptotic pore formation. Here, we characterize GSDMD function in live cells and in vitro We show that the N-terminal fragment of caspase-1-cleaved GSDMD rapidly targets the membrane fraction of macrophages and that it induces the formation of a plasma membrane pore. In vitro, the N-terminal fragment of caspase-1-cleaved recombinant GSDMD tightly binds liposomes and forms large permeability pores. Visualization of liposome-inserted GSDMD at nanometer resolution by cryo-electron and atomic force microscopy shows circular pores with variable ring diameters around 20 nm. Overall, these data demonstrate that GSDMD is the direct and final executor of pyroptotic cell death.
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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 [633]
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- Authors
- Sborgi, L., Rühl, S., Mulvihill, E., Pipercevic, J., Heilig, R., Stahlberg, H., Farady, C. J., Müller, D. J., Broz, P., & Hiller, S.
- Affiliations
- University of Basel (CH)
- ETH Zurich (CH)
- Novartis (Switzerland) (CH)
- Corresponding author
- Hiller, Sebastian
- ORCID
- Venue
- The EMBO Journal
- Published
- 2016-07-14
- Volume
- 35
- Issue
- 16
- Pages
- 1766-1778
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC5010048
- OpenAlex
- W2461915818
- Cited by
- 1,152
- References
- 45
- Citations by year
- 2026: 84 · 2025: 98 · 2024: 154 · 2023: 167 · 2022: 153 · 2021: 147 · 2020: 101 · 2019: 99 · 2018: 75 · 2017: 61 · 2016: 13
- FWCI
- 42.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- edoc (University of Basel) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc-nd)
- ETH Zürich Research Collection
- Funders
- European Research Council (MOMP 281764)
- Swiss National Science Foundation (PP00P3_139120/1)
- Marie Curie Cancer Care (FP7‐PEOPLE‐2012‐ITN, Project 317348)
- 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
- pyroptosis, gasdermin D, pore formation, inflammasome, plasma membrane permeability, macrophages
- MeSH terms
- Pyroptosis, Gasdermins, Cell Line, Cell Membrane, Humans, Liposomes, Neoplasm Proteins, Permeability, Microscopy, Atomic Force, Caspase 1, Cryoelectron Microscopy, Phosphate-Binding Proteins, Intracellular Signaling Peptides and Proteins
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