Journal Article

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

Stocks, Hannah, Krönke, Martin, Schwarzer, Robin, Kashkar, Hamid, Schiffmann, Lars M., Fritsch, Melanie, Stair, Neil, Schorn, Fabian, Werthenbach, J. Paul, Pasparakis, Manolis, Albert, Marie-Christine, Seeger, Jens M., Günther, Saskia D., Lamkanfi, Mohamed

2019

Overview

Caspase-8 is the initiator caspase of extrinsic apoptosis 1 , 2 and inhibits necroptosis mediated by RIPK3 and MLKL. Accordingly, caspase-8 deficiency in mice causes embryonic lethality 3 , which can be rescued by deletion of either Ripk3 or Mlkl 4 – 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 −/− mice 3 , 7 , Casp8 C362S/C362S mouse embryos died after endothelial cell necroptosis leading to cardiovascular defects. MLKL deficiency rescued the cardiovascular phenotype but unexpectedly caused perinatal lethality in Casp8 C362S/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 mice 8 . 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 Casp8 C362S/C362S Mlkl −/− Asc −/− or Casp8 C362S/C362S Mlkl −/− 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. The enzymatic activity of caspase-8 controls apoptosis, necroptosis and pyroptosis, and prevents tissue damage during embryonic development and adulthood in mice.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/2 / 13/21 / 14 / 14/19 / 631/250 / 631/250/1933 / 64/60 / 82/51 / Activation / Analysis / Animals / Antigens / Apoptosis / Apoptosis - genetics / Caspase 8 - genetics / Caspase 8 - metabolism / Caspase-1 / Caspase-8 / Catalytic activity / Cell Line / Cells, Cultured / Clonal deletion / Control / Cytokines / Damage prevention / Developmental stages / Embryogenesis / Embryonic growth stage / Embryos / Endothelial cells / Endothelium / Enzyme Activation - genetics / Epithelial cells / Gene Expression Profiling / Gene Knockout Techniques / Genotype & phenotype / HEK293 Cells / Homeostasis / Humanities and Social Sciences / Humans / Inflammasomes / Inflammasomes - metabolism / Intestinal Mucosa - cytology / Intestinal Mucosa - enzymology / Intestine / Keratin / Keratinocytes - cytology / Keratinocytes - pathology / Lethality / Mice / Molecular biology / Molecular machines / multidisciplinary / Mutation / Necroptosis / Necroptosis - genetics / Necrosis / Phenotypes / Proteins / Pyroptosis / Pyroptosis - genetics / Receptor, TIE-2 - genetics / Receptor, TIE-2 - metabolism / Science / Science (multidisciplinary) / Weaning