Fig. 1

Caspase activation pathways [131]. Caspase activation by the extrinsic pathway (route 1) involves the binding of extracellular death ligands (such as FasL or tumor necrosis factor-α (TNFα)) to transmembrane death receptors. Engagement of death receptors with their cognate ligands provokes the recruitment of adaptor proteins, such as the Fas-associated death domain protein (FADD), which in turn recruit and aggregate several molecules of caspase-8, thereby promoting its autoprocessing and activation. Active caspase-8 then proteolytically processes and activates caspase-3 and caspase-7, provoking further caspase activation events that culminate in substrate proteolysis and cell death. In some situations, extrinsic death signals can crosstalk with the intrinsic pathway through caspase-8-mediated proteolysis of the BH3-only protein BID (BH3-interacting domain death agonist). Truncated BID (tBID) can promote mitochondrial cytochrome c release and assembly of the apoptosome (comprising ~7 molecules of apoptotic protease-activating factor-1 (APAF1) and the same number of caspase-9 homodimers). In the intrinsic pathway (route 2), diverse stimuli that provoke cell stress or damage typically activate one or more members of the BH3-only protein family. BH3-only proteins act as pathway-specific sensors for various stimuli and are regulated in distinct ways. BH3-only protein activation above a crucial threshold overcomes the inhibitory effect of the anti-apoptotic B cell lymphoma-2 (BCL-2) family members and promotes the assembly of BAK–BAX oligomers within mitochondrial outer membranes. These oligomers permit the efflux of intermembrane space proteins, such as cytochrome c, into the cytosol. On release from mitochondria, cytochrome c can seed apoptosome assembly. Active caspase-9 then propagates a proteolytic cascade of further caspase activation events. The granzyme B-dependent route to caspase activation (route 3) involves the delivery of this protease into the target cell through specialized granules that are released from cytotoxic T lymphocytes (CTL) or natural killer (NK) cells. CTL and NK granules contain numerous granzymes as well as a poreforming protein, perforin, which oligomerizes in the membranes of target cells to permit entry of the granzymes. Granzyme B, similar to the caspases, also cleaves its substrates after Asp residues and can process BID as well as caspase-3 and caspase-7 to initiate apoptosis. BAD BCL-2 antagonist of cell death, BAK BCL-2-antagonist/killer-1, BAX BCL-2-associated X protein, BID BH3-interacting domain death agonist, BIK BCL-2-interacting killer, BIM BCL-2-like-11, BMF BCL-2 modifying factor, HRK harakiri (also known as death protein-5), PUMA BCL-2 binding component-3