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

Melanie Fritsch, Saskia D. Günther, Robin Schwarzer, Marie-Christine Albert, Fabian Schorn, J. Paul Werthenbach, Lars M. Schiffmann, Neil Stair, Hannah Stocks, Jens M. Seeger, Mohamed Lamkanfi, Martin Krönke, Manolis Pasparakis and Hamid Kashkar ()
Additional contact information
Melanie Fritsch: University of Cologne
Saskia D. Günther: University of Cologne
Robin Schwarzer: University of Cologne
Marie-Christine Albert: University of Cologne
Fabian Schorn: University of Cologne
J. Paul Werthenbach: University of Cologne
Lars M. Schiffmann: University of Cologne
Neil Stair: University of Cologne
Hannah Stocks: University of Cologne
Jens M. Seeger: University of Cologne
Mohamed Lamkanfi: Ghent University
Martin Krönke: University of Cologne
Manolis Pasparakis: University of Cologne
Hamid Kashkar: University of Cologne

Nature, 2019, vol. 575, issue 7784, 683-687

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1770-6

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