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BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1β Maturation in Macrophages.
Chauhan, Dhruv Bartok, Eva Gaidt, Moritz M Bock, Florian J Herrmann, Jennifer Seeger, Jens M Broz, Petr Beckmann, Roland Kashkar, Hamid Tait, Stephen W G
Chauhan, Dhruv
Bartok, Eva
Gaidt, Moritz M
Bock, Florian J
Herrmann, Jennifer
Seeger, Jens M
Broz, Petr
Beckmann, Roland
Kashkar, Hamid
Tait, Stephen W G
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2018-11-27
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Abstract
IL-1β is a cytokine of pivotal importance to the orchestration of inflammatory responses. Synthesized as an inactive pro-cytokine, IL-1β requires proteolytic maturation to gain biological activity. Here, we identify intrinsic apoptosis as a non-canonical trigger of IL-1β maturation. Guided by the discovery of the immunomodulatory activity of vioprolides, cyclic peptides isolated from myxobacteria, we observe IL-1β maturation independent of canonical inflammasome pathways, yet dependent on intrinsic apoptosis. Mechanistically, vioprolides inhibit MCL-1 and BCL2, which in turn triggers BAX/BAK-dependent mitochondrial outer membrane permeabilization (MOMP). Induction of MOMP results in the release of pro-apoptotic factors initiating intrinsic apoptosis, as well as the depletion of IAPs (inhibitors of apoptosis proteins). IAP depletion, in turn, operates upstream of ripoptosome complex formation, subsequently resulting in caspase-8-dependent IL-1β maturation. These results establish the ripoptosome/caspase-8 complex as a pro-inflammatory checkpoint that senses the perturbation of mitochondrial integrity.
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Cell Rep. 2018 Nov 27;25(9):2354-2368.e5. doi: 10.1016/j.celrep.2018.10.087
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en
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2211-1247
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Attribution-NonCommercial-ShareAlike 4.0 International