Schematic overview of the human tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) apoptosis pathway. Binding of TRAIL to TRAIL-R1 and/or TRAIL-R2 leads to receptor trimerisation and formation of the death-inducing signalling complex (DISC). The adaptor protein Fas-associated death domain (FADD) is recruited to the DISC where the death domains (DD) of both proteins interact. Subsequently, pro-caspases 8 and 10 are recruited to the DISC where they interact with FADD via their death effector domains (DEDs). DISC-activated caspases 8 and 10 then trigger a caspase cascade by cleavage of caspase-3. In addition, Bid is cleaved into tBid, which initiates the mitochondrial apoptosis pathway leading to release of cytochrome c (CytC) and second mitochondria derived activator of caspases/direct IAP binding protein with low pI (Smac/DIABLO) from the mitochondria. CytC, together with apoptotic protease activating factor 1 (Apaf-1) forms the apoptosome, an activation platform for caspase-9. Smac/Diablo counteracts the inhibitory function of X-linked inhibitor of apoptosis protein (XIAP), thereby allowing for full activation of caspases 3 and 9, ultimately leading to cell death. The intrinsic, Bcl-2-controlled, pathway is also triggered after extensive DNA damage. BH3-only proteins PUMA and Noxa are up-regulated, thereby altering the ratio of pro-apoptotic and anti-apoptotic Bcl-2-family members, allowing for mitochondrial depolarization and cell death. c-FLIP, cellular FLICE inhibitory protein.
