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The core intraCellular machinery that regulates and executes apoptosis in vertebrates comprises families of proteins that interact with each other and with intracellular organelles. In many cases, information from the environment is relayed to a central 'apoptosis rheostat' at the mitochondrion by stimulus-specific induction, modification or movement of pro-apoptotic 'BH3 domain-only' members of the Bcl-2 family (including Bid,Bad, Bim, Bik/Nbk, Blk, Hrk, Bnip3, Nix, NOXA, PUMA and Bcl-GS).
Once 'activated', these proteins are thought to facilitate, through many mechanisms, the asseMBLy of pro-apoptotic 'multi-domain' members of the Bcl-2 family (Bax, Bak, Bok/Mtd, Bcl-rambo) into heterodimeric units or 'pores' in the outer mitochondrial membrane. This causes the release of numerous 'apoptogenic' factors, which include cytochrome c, Smac/DIABLO, apoptosis-inducing factor (Aif) and endonuclease-G (endo-G), from the mitochondria into the cytosol through a process that can be blocked by anti-apoptotic multi-domain Bcl-2 family members (Bcl-2, Bcl-xL, Bcl-w, Mcl-1, A1/Bfl1 and Bcl-B).
Cytochrome c release is essential for the generation of the 'apoptosome', containing Apaf-1 and pro-caspase-9. Once formed, the apoptosome initiates the effector caspase cascade (which usually involves caspases-2, -3, -6 and/or -7) after auto- or transcatalytic activation of the most apical (initiator) enzyme, caspase-9. A checkpoint, which is composed of a family of gene products referred to as inhibitor-of-apoptosis proteins (IAPs), prevents premature or unwanted activation of apoptosis by repression of caspase activation/activity. But this survival checkpoint is subverted by the mitochondrial release of Smac/DIABLO, which dissociates IAPs from caspase-9 and permits it to activate effector caspases.
In the case of death-receptor-initiated apoptosis, two distinct intracellular pathways can be engaged after pro-caspase-8 becomes activated. In 'type-I cells', sufficient levels of caspase-8 are GENErated to directly initiate the effector caspase cascade. In 'type-II cells', low levels of caspase-8cleave the pro-apoptotic Bcl-2 family member Bid to a truncated protein (tBid) that works with Bax and Bak to 'damage' mitochondria, promote formation of the apoptosome and trigger effector caspase activation.
