Splitting the apoptosome.
Assembly of the apoptosome in response to mitochondrial permeabilization, the hallmark of the intrinsic apoptotic pathway, involves binding of cytochrome c to Apaf1, recruitment and auto-processing of the apical/signaling pro-caspase-9, and coupled activation of downstream/executioner caspases like caspase 3. Evidence now indicates that certain apoptotic cascades can bypass the apoptosome and activate caspase-9 independent of the mitochondria. Recently, we have demonstrated that caspase-9 can be activated in Apaf1-mutant primary myoblasts, but not fibroblasts, in response to stimuli that are known to act via the mitochondria. Thus, apoptosomal activation of caspase-9 seems to represent only one of the routes for its activation; other pathways, some of which are yet to be discovered, can bypass the requirement for Apaf1 and activate caspase-9 in a tissue and context specific manner.
Ho
Andrew T
AT
Division of Cell & Molecular Biology, Toronto General Research Institute-University Health Network, Toronto, Ontario, Canada.
Zacksenhaus
Eldad
E
D000818:Animals; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D017173:Caenorhabditis elegans; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism
C506592:APAF1 protein, human; C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D011506:Proteins; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases