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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.; Müller, Rolf and Hornung, Veit (2018): BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1beta Maturation in Macrophages. In: Cell Reports, Vol. 25, No. 9, P2354-2368.E5

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IL-1beta is a cytokine of pivotal importance to the orchestration of inflammatory responses. Synthesized as an inactive pro-cytokine, IL-1beta requires proteolytic maturation to gain biological activity. Here, we identify intrinsic apoptosis as a non-canonical trigger of IL-1beta maturation. Guided by the discovery of the immunomodulatory activity of vioprolides, cyclic peptides isolated from myxobacteria, we observe IL-1beta 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-1beta 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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