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GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death

Sborgi, Lorenzo and Rühl, Sebastian and Mulvihill, Estefania and Pipercevic, Joka and Heilig, Rosalie and Stahlberg, Henning and Farady, Christopher J. and Müller, Daniel J. and Broz, Petr and Hiller, Sebastian. (2016) GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. The EMBO Journal, 35 (16). pp. 1766-1778.

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Infection Biology (Broz)
05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Hiller)
05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Stahlberg)
UniBasel Contributors:Broz, Petr and Sborgi, Lorenzo and Rühl, Sebastian and Pipercevic, Joka and Heilig, Rosalie and Stahlberg, Henning and Hiller Odermatt, Sebastian
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
ISSN:0261-4189
e-ISSN:1460-2075
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:21 Dec 2017 07:10
Deposited On:03 Jan 2017 08:07

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