Caspase-8 in apoptosis: the beginning of "the end"?
Caspase-8 is a member of the cysteine proteases, which are implicated in apoptosis and cytokine processing. Like all caspases, caspase-8 is synthesized as an inactive single polypeptide chain zymogen procaspase and is activated by proteolytic cleavage, through either autoactivation after recruitment into a multimeric complex or trans-cleavage by other caspases. Thus, ligand binding-induced trimerization of death receptors results in recruitment of the receptor-specific adapter protein Fas-associated death domain (FADD), which then recruits caspase-8. Activated caspase-8 is known to propagate the apoptotic signal either by directly cleaving and activating downstream caspases or by cleaving the BH3 Bcl2-interacting protein, which leads to the release of cytochrome c from mitochondria, triggering activation of caspase-9 in a complex with dATP and Apaf-1. Activated caspase-9 then activates further "downstream caspases," including caspase-8. Knockout data indicate that caspase-8 is required for killing induced by the death receptors Fas, tumor necrosis factor receptor 1, and death receptor 3. Moreover, caspase-8-/- mice die in utero as a result of defective development of heart muscle and display fewer hematopoietic progenitor cells, suggesting that the FADD/caspase-8 pathway is absolutely required for growth and development of specific cell types.
Kruidering
M
M
UCSF Cancer Center, San Francisco, California 94115, USA.
Evan
G I
GI
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D029681:Arabidopsis Proteins; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism* / Q000502:physiology*; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D044943:Fatty Acid Desaturases / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D011506:Proteins / Q000378:metabolism
C506592:APAF1 protein, human; C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D029681:Arabidopsis Proteins; D003574:Cytochrome c Group; D008024:Ligands; D011506:Proteins; D000255:Adenosine Triphosphate; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases