Structural basis of GSDME pore formation and its regulation by S-palmitoylation.

Authors

Gang Du, Julian F Ehrmann, Judy Lieberman, Hao Wu

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 35. Pages e2614339123. Epub Aug 24, 2026.

Abstract

Pyroptosis is defined as gasdermin-mediated lytic programmed cell death. Gasdermin E (GSDME), a substrate of the apoptotic caspase-3, can convert apoptosis into pyroptosis, with critical roles in antitumor immunity and chemotherapy-induced tissue damage. Despite its importance, the structural mechanism of GSDME pore formation and its regulation by posttranslational modifications remain largely unknown. Here, we present the cryo-electron microscopy (cryo-EM) structure at 3.16 Å resolution of the human GSDME N-terminal (NT) pore using proteins expressed from mammalian cells. The structure reveals a GSDME-NT pore assembled mainly as a 28-subunit homo-oligomer, and a dramatic conformational rearrangement from the autoinhibited state, with refolding of the two β-hairpins in each monomer to form a membrane-spanning β-barrel with an acidic conduit. Unexpectedly, we identify endogenous S-palmitoylation of C45, C168, and C180, required for membrane binding and pore formation. In addition, extra cryo-EM densities are visible adjacent to the C45 side chain, potentially corresponding to the flexibly linked palmitate chain. Structure-guided mutagenesis demonstrates that these palmitoylation sites synergistically control pore formation. The structure served as a molecular blueprint for analyzing cancer-associated mutations, known to disrupt GSDME function. These mutations cluster at functional hotspots in the oligomerization interfaces, membrane-contact regions, and the β-barrel, where they disrupt pore integrity. Collectively, our findings establish palmitoylation as an obligatory licensing step for membrane binding and pore formation, provide structural visualization of a palmitoylated gasdermin, and reveal how cancer-associated mutations impair pyroptotic function. This structure and these insights will be useful for developing strategies that target GSDME to treat cancer and inflammatory disease.

PMID:
42636365
Bibliographic data and abstract were imported from PubMed on 25 Aug 2026.

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