Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Chauhan, Dhruv UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartok, Eva UNSPECIFIED orcid.org/0000-0003-0556-1950 UNSPECIFIED Gaidt, Moritz M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bock, Florian J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Herrmann, Jennifer UNSPECIFIED orcid.org/0000-0003-3398-9938 UNSPECIFIED Seeger, Jens M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Broz, Petr UNSPECIFIED orcid.org/0000-0002-2334-7790 UNSPECIFIED Beckmann, Roland UNSPECIFIED UNSPECIFIED UNSPECIFIED Kashkar, Hamid UNSPECIFIED UNSPECIFIED UNSPECIFIED Tait, Stephen W. G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Hornung, Veit UNSPECIFIED orcid.org/0000-0002-4150-194X UNSPECIFIED
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:	Keywords Language NLRP3 INFLAMMASOME ACTIVATION; CELL-DEATH; GASDERMIN D; B-CELL; CASPASE-8; INHIBITOR; RECEPTORS; RELEASE; TRANSLATION; VIOPROLIDES Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16532