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
  • 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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