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Extrinsic and intrinsic apoptosis activate pannexin‐1 to drive NLRP 3 inflammasome assembly
Author(s) -
Chen Kaiwen W,
Demarco Benjamin,
Heilig Rosalie,
Shkarina Kateryna,
Boettcher Andreas,
Farady Christopher J,
Pelczar Pawel,
Broz Petr
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019101638
Subject(s) - biology , inflammasome , pannexin , microbiology and biotechnology , caspase 1 , apoptosis , genetics , receptor , gap junction , intracellular , connexin
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, TAK 1 inhibitors and BH 3 mimetics promote caspase‐8 or caspase‐9‐dependent inflammatory cell death and NLRP 3 inflammasome activation. However, the mechanism by which caspase‐8 or caspase‐9 triggers cell lysis and NLRP 3 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 NLRP 3 inflammasome activation during caspase‐8 or caspase‐9‐dependent apoptosis.