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Cell Rep. 2018 Nov 27;25(9):2354-2368.e5. doi: 10.1016/j.celrep.2018.10.087.

BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1β Maturation in Macrophages.

Author information

1
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
2
Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53127 Bonn, Germany.
3
Cancer Research UK Beatson Institute, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
4
Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, 66123 Saarbrücken, Germany; Helmholtz Centre for Infection Research and Department of Pharmacy, Saarland University, 66123 Saarbrücken, Germany; German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, 38124 Braunschweig, Germany.
5
Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
6
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
7
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany. Electronic address: hornung@genzentrum.lmu.de.

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.

KEYWORDS:

BAX/BAK; BCL2; IAP depletion; IL-1β; MCL-1; NLRP3; caspase-8; intrinsic apoptosis; ripoptosome

PMID:
30485805
DOI:
10.1016/j.celrep.2018.10.087
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