Authors
Shirin Kappelhoff, Michael Holtmannspötter, Stefan L Schaefer, Eleonora G Margheritis, Özgün Doga Asik, Nadine Gehle, Hannah Veit, John S H Danial, Rico Franzkoch, Sebastian Strauss, Jonatan Alvelid, Agnes Koerfer, Christian Eggeling, Olympia E Psathaki, Ralf Jungmann, Rainer Kurre, Gerhard Hummer, Jacob Piehler, Katia Cosentino
Published in
Science advances. Volume 12. Issue 28. Pages eaee4587. Jul 10, 2026. Epub Jul 10, 2026.
Abstract
Gasdermin D (GSDMD) executes pyroptosis by forming membrane pores, yet how these structures assemble and are regulated in cells has remained technically inaccessible. We introduce polymer-supported plasma membranes (PSPMs), which preserve native PM properties while providing cytosolic access for nanoscopic imaging. Combining PSPMs with DNA-PAINT super-resolution microscopy, we visualize human and mouse GSDMD nanostructures directly at the PM of pyroptotic cells and uncover species-specific differences in pore size. Quantitative analyses reveal that GSDMD assembles into heterogeneous macromolecular architectures, including ring-shaped structures, which correlate with PM permeabilization. The palmitoylation-deficient C191A mutant retains minor membrane association but fails to form complete rings, indicating that ring assembly, more than membrane binding, determines pore activity. Last, we identify PI(3,4,5)P3 as a key regulator of pore stabilization. Its early increase during pyroptosis promotes growth of large rings, and mutations in PI(3,4,5)P3-interacting residues undermine assembly. These findings define the native architecture of GSDMD pores and reveal lipid-dependent stabilization as a central mechanism regulating pyroptotic membrane permeabilization.
PMID:
42430474
Bibliographic data and abstract were imported from PubMed on 11 Jul 2026.
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