caa a22 4500 551458186 CHVBK 20190303134137.0 cr unu---uuuuu 181215e20181127xx s 000 0 eng 10.1016/j.celrep.2018.10.087 doi (SERVAL)BIB_6A46ECA09273 30485805 pmid 000451469100006 isiid BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1β Maturation in Macrophages [Elektronische Daten] [D. Chauhan, E. Bartok, M.M. Gaidt, F.J. Bock, J. Herrmann, J.M. Seeger, P. Broz, R. Beckmann, H. Kashkar, SWG Tait, R. Müller, V. Hornung] 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. Chauhan D. aut Bartok E. aut Gaidt M.M. aut Bock F.J. aut Herrmann J. aut Seeger J.M. aut Broz P. aut Beckmann R. aut Kashkar H. aut Tait SWG aut Müller R. aut Hornung V. aut Cell reports 25/9(2018-11-27), 2354-2368.e5 25:9<2354-2368.e5 2018 25 1 article serval SERVAL 700 1- Chauhan D. aut SERVAL 700 1- Bartok E. aut SERVAL 700 1- Gaidt M.M. aut SERVAL 700 1- Bock F.J. aut SERVAL 700 1- Herrmann J. aut SERVAL 700 1- Seeger J.M. aut SERVAL 700 1- Broz P. aut SERVAL 700 1- Beckmann R. aut SERVAL 700 1- Kashkar H. aut SERVAL 700 1- Tait SWG aut SERVAL 700 1- Müller R. aut SERVAL 700 1- Hornung V. aut SERVAL 773 0- Cell reports 25/9(2018-11-27), 2354-2368.e5 25:9<2354-2368.e5 2018 25 BK010053 XK010053 XK010000 SERVAL SERVAL SERVAL article