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. Epub 2019 Nov 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Caspase 8 / genetics*
  • Caspase 8 / metabolism*
  • Cell Line
  • Cells, Cultured
  • Enzyme Activation / genetics
  • Gene Expression Profiling
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Inflammasomes / metabolism
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / enzymology
  • Keratinocytes / cytology
  • Keratinocytes / pathology
  • Mice
  • Mutation
  • Necroptosis / genetics*
  • Pyroptosis / genetics*
  • Receptor, TIE-2 / genetics
  • Receptor, TIE-2 / metabolism


  • Inflammasomes
  • Receptor, TIE-2
  • Tek protein, mouse
  • Caspase 8