2. Academic Validation
  3. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis

Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis

  • Nature. 2019 Nov;575(7784):683-687. doi: 10.1038/s41586-019-1770-6.
Melanie Fritsch 1,  Saskia D Günther 1,  Robin Schwarzer 2,  Marie-Christine Albert 1,  Fabian Schorn 1,  J Paul Werthenbach 1,  Lars M Schiffmann 1 3,  Neil Stair 1 2,  Hannah Stocks 1,  Jens M Seeger 1,  Mohamed Lamkanfi 4 5,  Martin Krönke 1,  Manolis Pasparakis 2 6,  Hamid Kashkar 7 8
Affiliations

Affiliations

  • 1 Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), CECAD Research Center, University of Cologne, Cologne, Germany.
  • 2 Institute for Genetics, CECAD Research Center, University of Cologne, Cologne, Germany.
  • 3 Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany.
  • 4 Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium.
  • 5 VIB Center for Inflammation Research, Ghent, Belgium.
  • 6 Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
  • 7 Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), CECAD Research Center, University of Cologne, Cologne, Germany. [email protected].
  • 8 Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. [email protected].
PMID: 31748744 DOI: 10.1038/s41586-019-1770-6
Abstract

Caspase-8 is the initiator Caspase of extrinsic Apoptosis1,2 and inhibits Necroptosis mediated by RIPK3 and MLKL. Accordingly, Caspase-8 deficiency in mice causes embryonic lethality3, which can be rescued by deletion of either Ripk3 or Mlkl4-6. Here we show that the expression of enzymatically inactive CASP8(C362S) causes embryonic lethality in mice by inducing Necroptosis and Pyroptosis. Similar to Casp8-/- mice3,7, Casp8C362S/C362S mouse embryos died after endothelial cell Necroptosis leading to cardiovascular defects. MLKL deficiency rescued the cardiovascular phenotype but unexpectedly caused perinatal lethality in Casp8C362S/C362S mice, indicating that CASP8(C362S) causes necroptosis-independent death at later stages of embryonic development. Specific loss of the catalytic activity of Caspase-8 in intestinal epithelial cells induced intestinal inflammation similar to intestinal epithelial cell-specific Casp8 knockout mice8. Inhibition of Necroptosis by additional deletion of Mlkl severely aggravated intestinal inflammation and caused premature lethality in Mlkl knockout mice with specific loss of Caspase-8 catalytic activity in intestinal epithelial cells. Expression of CASP8(C362S) triggered the formation of ASC specks, activation of Caspase-1 and secretion of IL-1β. Both embryonic lethality and premature death were completely rescued in Casp8C362S/C362SMlkl-/-Asc-/- or Casp8C362S/C362SMlkl-/-Casp1-/- mice, indicating that the activation of the inflammasome promotes CASP8(C362S)-mediated tissue pathology when Necroptosis is blocked. Therefore, Caspase-8 represents the molecular switch that controls Apoptosis, Necroptosis and Pyroptosis, and prevents tissue damage during embryonic development and adulthood.

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