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Microsynth seqlab12/21/2023 Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Therefore, caspase-8 represents the molecular switch that controls apoptosis, necroptosis and pyroptosis, and prevents tissue damage during embryonic development and adulthood. 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. Expression of CASP8(C362S) triggered the formation of ASC specks, activation of caspase-1 and secretion of IL-1β. 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. 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. 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. Similar to Casp8 −/− mice 3, 7, Casp8 C362S/C362S mouse embryos died after endothelial cell necroptosis leading to cardiovascular defects. Here we show that the expression of enzymatically inactive CASP8(C362S) causes embryonic lethality in mice by inducing necroptosis and pyroptosis. Accordingly, caspase-8 deficiency in mice causes embryonic lethality 3, which can be rescued by deletion of either Ripk3 or Mlkl 4, 5, 6. Caspase-8 is the initiator caspase of extrinsic apoptosis 1, 2 and inhibits necroptosis mediated by RIPK3 and MLKL.
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