| First Author | Fritsch M | Year | 2019 |
| Journal | Nature | Volume | 575 |
| Issue | 7784 | Pages | 683-687 |
| PubMed ID | 31748744 | Mgi Jnum | J:285930 |
| Mgi Id | MGI:6401035 | Doi | 10.1038/s41586-019-1770-6 |
| Citation | Fritsch M, et al. (2019) Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature 575(7784):683-687 |
| abstractText | 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-1beta. 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. |
