BAX/BAK induced apoptosis results in caspase-8 dependent IL-1β maturation in macrophages

Chauhan, D. et al. (2018) BAX/BAK induced apoptosis results in caspase-8 dependent IL-1β maturation in macrophages. Cell Reports, 25(9), 2354-2368.e5. (doi: 10.1016/j.celrep.2018.10.087) (PMID:30485805)

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.

• Item Type: Articles
• Additional Information: This work was supported by a grant from the DZIF 09.804 (German Center for Infection Research) to V.H.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bock, Dr Florian and Tait, Professor Stephen
• Authors: Chauhan, D., Bartok, E., Gaidt, M. M., Bock, F. J., Herrmann, J., Seeger, J. M., Broz, P., Beckmann, R., Kashkar, H., Tait, S. W.G., Müller, R., and Hornung, V.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Reports
• Publisher: Elsevier (Cell Press)
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Cell Reports 25(9): 2354-2368.e5
• Publisher Policy: Reproduced under a Creative Commons License