The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity.
- Schneider KS Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany.
- Groß CJ Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; BIOSS Centre for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany.
- Dreier RF Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
- Saller BS Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
- Mishra R Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, 81675 Munich, Germany.
- Gorka O Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
- Heilig R Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
- Meunier E Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
- Dick MS Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
- Ćiković T Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, 81675 Munich, Germany.
- Sodenkamp J Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, 81675 Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany.
- Médard G Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany.
- Naumann R Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
- Ruland J Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, 81675 Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany; German Center for Infection Research (DZIF), partner site Munich, 81675 Munich, Germany.
- Kuster B Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany; Center for Integrated Protein Science Munich (CIPSM), 81377 Munich, Germany.
- Broz P Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland; Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
- Groß O Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; BIOSS Centre for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany; Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, 81675 Munich, Germany. Electronic address: olaf.gross@uniklinik-freiburg.de.
- 2017-12-28
Published in:
- Cell reports. - 2017
ASC
IL-1
caspase-1
caspase-8
gasdermin
inflammasome
pyroptosis
regulated necrosis
Animals
Apoptosis Regulatory Proteins
Caspase 1
Caspase 8
Caspase Inhibitors
Enzyme Activation
Francisella
Immunity, Innate
Inflammasomes
Interleukin-1
Interleukin-1beta
Mice, Inbred C57BL
Pyroptosis
English
Inflammasomes activate the protease caspase-1, which cleaves interleukin-1β and interleukin-18 to generate the mature cytokines and controls their secretion and a form of inflammatory cell death called pyroptosis. By generating mice expressing enzymatically inactive caspase-1C284A, we provide genetic evidence that caspase-1 protease activity is required for canonical IL-1 secretion, pyroptosis, and inflammasome-mediated immunity. In caspase-1-deficient cells, caspase-8 can be activated at the inflammasome. Using mice either lacking the pyroptosis effector gasdermin D (GSDMD) or expressing caspase-1C284A, we found that GSDMD-dependent pyroptosis prevented caspase-8 activation at the inflammasome. In the absence of GSDMD-dependent pyroptosis, the inflammasome engaged a delayed, alternative form of lytic cell death that was accompanied by the release of large amounts of mature IL-1 and contributed to host protection. Features of this cell death modality distinguished it from apoptosis, suggesting it may represent a distinct form of pro-inflammatory regulated necrosis.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1016/j.celrep.2017.12.018
- PMID 29281832
- Persistent URL
- https://sonar.ch/global/documents/299291
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