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

Details

Serval ID
serval:BIB_5D469A46BEF0
Type
Article: article from journal or magazin.
Collection
Publications
Title
GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death.
Journal
The EMBO Journal
Author(s)
Sborgi L., Rühl S., Mulvihill E., Pipercevic J., Heilig R., Stahlberg H., Farady C.J., Müller D.J., Broz P., Hiller S.
ISSN
1460-2075 (Electronic)
ISSN-L
0261-4189
Publication state
Published
Issued date
2016
Peer-reviewed
Oui
Volume
35
Number
16
Pages
1766-1778
Language
english
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.

Keywords
Caspase 1/metabolism, Cell Line, Cell Membrane/metabolism, Cryoelectron Microscopy, Humans, Liposomes/chemistry, Liposomes/ultrastructure, Microscopy, Atomic Force, Neoplasm Proteins/metabolism, Permeability, Pyroptosis, atomic force microscopy, cell death, gasdermin, inflammasomes, inflammation, pyroptosis
Pubmed
Web of science
Open Access
Yes
Create date
25/10/2017 10:05
Last modification date
20/08/2019 14:15
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