CASP8
Caspase-8 is a protein in humans that is encoded by CASP8 gene. Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein.
Caspase-8, encoded by gene CASP8, is a member of the cysteine proteases that specifically cleave substrates at sites located after aspartic acid residues in target amino acid sequences. Like all caspases, caspase‐8 is synthesized as an inactive monomer procaspase. Caspase-8 activation requires not only proteolytic processing but also the dimerization process. Caspase-8 carries a large N-terminal prodomain with a DED (death effector domain) followed by the catalytic domain containing a large and small subunit separated by a linker region. Ligation of Fas by Fas Ligand initiates recruitment of caspase-8 to the membrane-bound DISC (death-inducing signaling complex) via the adaptor protein FADD (FAS-associated death domain) through their death effector domain (DED), respectively [3]. The DISC is formed at the cytoplasmic tail of the engaged DR that also includes the adapter protein FAS-associated death domain (FADD) or TNFR-associated death domain (TRADD). Recruitment of caspase-8 monomers results in dimerization and activation. Caspase-8 activation also occurs through a feedback loop derived from the intrinsic apoptotic pathway. Caspase-3 and caspase-6 can facilitate the transition of pro-caspase-8 to be an active dimer form via proteolysis. As an initiator caspase, active caspase-8 is released to the cytosol and cleaves downstream effector caspases. In some cell types, caspase-8 cleaves the BH3-only protein Bid to promote MOMP that ultimately induces cytochrome c leakage, caspase-9 activation, and subsequent apoptosis. Activated caspase‐9 further stimulates further downstream caspases, including caspase‐8. Melanie Fritsch et al. uncovered that caspase-8 represents the molecular switch that controls apoptosis, necroptosis, and pyroptosis, and prevents tissue damage during embryonic development and adulthood.
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