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

  • Chauhan D Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • Bartok E Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53127 Bonn, Germany.
  • Gaidt MM Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • Bock FJ 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.
  • Herrmann J 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.
  • Seeger JM 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.
  • Broz P Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
  • Beckmann R Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • Kashkar H 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.
  • Tait SWG 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.
  • Müller R 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.
  • Hornung V Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany. Electronic address: hornung@genzentrum.lmu.de.
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  • 2018-11-29
Published in:
  • Cell reports. - 2018
BAX/BAK
BCL2
IAP depletion
IL-1β
MCL-1
NLRP3
caspase-8
intrinsic apoptosis
ripoptosome
Animals
Apoptosis
Caspase 1
Caspase 8
Cell Survival
Enzyme Activation
Humans
Interleukin-1beta
L-Lactate Dehydrogenase
Macrophages
Mice
Mitochondrial Membranes
NLR Family, Pyrin Domain-Containing 3 Protein
Peptides, Cyclic
Permeability
Protein Synthesis Inhibitors
bcl-2 Homologous Antagonist-Killer Protein
bcl-2-Associated X Protein
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://susi.usi.ch/global/documents/100513
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