Caspases play in traffic

The unfolding of apoptosis involves the orchestrated proteolysis of hundreds of proteins,1 and to achieve efficacy the cell has evolved a three-step activation cascade. First, initiator caspases (caspases 8, 9, 10) are activated either by external death ligands triggering the formation of the death-inducing signaling complex (DISC; caspases 8 and 10) or by the release of cytochrome c from mitochondria provoking the assembly of the apoptosome (caspase-9).2 Once activated, the initiator caspases directly cleave executioner caspases 3 and 7, leading to their activation. The third step is the caspase-3-mediated activation of the executioner caspase-6, a peptidase with a substrate preference similar to that of initiator caspases. In this manner, the cell amplifies the proteolytic activity of caspases to swiftly cause cell demise.