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GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Sborgi Lorenzo, Rühl Sebastian, Mulvihill Estefania, Pipercevic Joka, Heilig Rosalie, Stahlberg Henning, Farady Christopher J, Müller Daniel J, Broz Petr, Hiller Sebastian,
Project Electron Microscopy of Membrane Proteins
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Original article (peer-reviewed)

Journal The EMBO journal
Volume (Issue) 35(16)
Page(s) 1766 - 78
Title of proceedings The EMBO journal
DOI 10.15252/embj.201694696

Abstract

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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