Extrinsic and intrinsic apoptosis activate pannexin-1 to drive NLRP3 inflammasome assembly.

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Serval ID
serval:BIB_5A6F55CD6B0E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Extrinsic and intrinsic apoptosis activate pannexin-1 to drive NLRP3 inflammasome assembly.
Journal
The EMBO journal
Author(s)
Chen K.W., Demarco B., Heilig R., Shkarina K., Boettcher A., Farady C.J., Pelczar P., Broz P.
ISSN
1460-2075 (Electronic)
ISSN-L
0261-4189
Publication state
Published
Issued date
15/05/2019
Peer-reviewed
Oui
Volume
38
Number
10
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Pyroptosis is a form of lytic inflammatory cell death driven by inflammatory caspase-1, caspase-4, caspase-5 and caspase-11. These caspases cleave and activate the pore-forming protein gasdermin D (GSDMD) to induce membrane damage. By contrast, apoptosis is driven by apoptotic caspase-8 or caspase-9 and has traditionally been classified as an immunologically silent form of cell death. Emerging evidence suggests that therapeutics designed for cancer chemotherapy or inflammatory disorders such as SMAC mimetics, TAK1 inhibitors and BH3 mimetics promote caspase-8 or caspase-9-dependent inflammatory cell death and NLRP3 inflammasome activation. However, the mechanism by which caspase-8 or caspase-9 triggers cell lysis and NLRP3 activation is still undefined. Here, we demonstrate that during extrinsic apoptosis, caspase-1 and caspase-8 cleave GSDMD to promote lytic cell death. By engineering a novel Gsdmd D88A knock-in mouse, we further demonstrate that this proinflammatory function of caspase-8 is counteracted by caspase-3-dependent cleavage and inactivation of GSDMD at aspartate 88, and is essential to suppress GSDMD-dependent cell lysis during caspase-8-dependent apoptosis. Lastly, we provide evidence that channel-forming glycoprotein pannexin-1, but not GSDMD or GSDME promotes NLRP3 inflammasome activation during caspase-8 or caspase-9-dependent apoptosis.
Keywords
3T3 Cells, Animals, Apoptosis/physiology, Apoptosis Regulatory Proteins/metabolism, Caspases/metabolism, Cells, Cultured, Connexins/physiology, Embryo, Mammalian, HEK293 Cells, HeLa Cells, Humans, Inflammasomes/metabolism, Intracellular Signaling Peptides and Proteins/metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Multiprotein Complexes/metabolism, NLR Family, Pyrin Domain-Containing 3 Protein/metabolism, Nerve Tissue Proteins/physiology, Phosphate-Binding Proteins/metabolism, Protein Binding, Protein Multimerization, Receptors, Estrogen/metabolism, Signal Transduction/physiology, NLRP3, apoptosis, gasdermin, pannexin‐1, pyroptosis
Pubmed
Web of science
Create date
09/05/2019 20:20
Last modification date
12/11/2020 7:08
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