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

Détails

ID Serval
serval:BIB_5D469A46BEF0
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death.
Périodique
The EMBO Journal
Auteur(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
Statut éditorial
Publié
Date de publication
2016
Peer-reviewed
Oui
Volume
35
Numéro
16
Pages
1766-1778
Langue
anglais
Résumé
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.

Mots-clé
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
Oui
Création de la notice
25/10/2017 11:05
Dernière modification de la notice
20/08/2019 15:15
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