Chauhan, Dhruv, Bartok, Eva ORCID: 0000-0003-0556-1950, Gaidt, Moritz M., Bock, Florian J., Herrmann, Jennifer ORCID: 0000-0003-3398-9938, Seeger, Jens M., Broz, Petr ORCID: 0000-0002-2334-7790, Beckmann, Roland, Kashkar, Hamid, Tait, Stephen W. G., Mueller, Rolf and Hornung, Veit ORCID: 0000-0002-4150-194X (2018). BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1 beta Maturation in Macrophages. Cell Reports, 25 (9). S. 2354 - 2374. CAMBRIDGE: CELL PRESS. ISSN 2211-1247

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Abstract

IL-1 beta is a cytokine of pivotal importance to the orchestration of inflammatory responses. Synthesized as an inactive pro-cytokine, IL-1 beta requires proteolytic maturation to gain biological activity. Here, we identify intrinsic apoptosis as a non-canonical trigger of IL-1 beta maturation. Guided by the discovery of the immunomodulatory activity of vioprolides, cyclic peptides isolated from myxobacteria, we observe IL-1 beta 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-1 beta maturation. These results establish the ripoptosome/caspase-8 complex as a pro-inflammatory checkpoint that senses the perturbation of mitochondrial integrity.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Chauhan, DhruvUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartok, EvaUNSPECIFIEDorcid.org/0000-0003-0556-1950UNSPECIFIED
Gaidt, Moritz M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bock, Florian J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herrmann, JenniferUNSPECIFIEDorcid.org/0000-0003-3398-9938UNSPECIFIED
Seeger, Jens M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Broz, PetrUNSPECIFIEDorcid.org/0000-0002-2334-7790UNSPECIFIED
Beckmann, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kashkar, HamidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tait, Stephen W. G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hornung, VeitUNSPECIFIEDorcid.org/0000-0002-4150-194XUNSPECIFIED
URN: urn:nbn:de:hbz:38-165324
DOI: 10.1016/j.celrep.2018.10.087
Journal or Publication Title: Cell Reports
Volume: 25
Number: 9
Page Range: S. 2354 - 2374
Date: 2018
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 2211-1247
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NLRP3 INFLAMMASOME ACTIVATION; CELL-DEATH; GASDERMIN D; B-CELL; CASPASE-8; INHIBITOR; RECEPTORS; RELEASE; TRANSLATION; VIOPROLIDESMultiple languages
Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/16532

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