Activation of initiator caspases in apoptosis.

摘要

The caspases are c&barbelow;ysteine-dependent aspartyl specific proteases responsible for initiating and carrying out apoptosis, a form of programmed cell death. Caspase activation is the "point of no return" commitment to cell death, and is initiated via either the extrinsic or intrinsic death pathway. The extrinsic death pathway is usually initiated via ligation of a cell-surface death receptors, whereas the intrinsic pathway is initiated in response to cellular stress signals.; My work has focused on understanding one aspect of the transmission of apoptotic signals---the activation of the initiator caspases. The death initiator caspase-8 is the first caspase to be activated in the extrinsic pathway, and then goes on to activate the downstream executioner caspases-3 and 7. My initial studies established that procaspase-8 exists within the cell as an inactive monomeric zymogen, and that its activation is mediated by dimerization at a multiprotein activating complex, the Death Inducing Signaling Complex (DISC). Furthermore, I found that cleavage is neither required nor sufficient for this activating event, in stark contrast to the activation mechanism of executioner caspases. Rather, once a single-chain caspase-8 has achieved its dimeric status, it is a catalytically competent enzyme. These findings have challenged ideas about caspase activation, and have contributed to the development of a unified model for the activation of all intiator caspases.; My recent studies have focused on defining the mechanism by which FLIP L activates procaspase-8. FLIPL is a homologue of this initiator caspase, but importantly lacks key elements required for caspase activity. My studies have revealed that FLIPL is an extremely efficient activator of procaspase-8. Furthermore, the ability of FLIPL to activate caspase-8 is completely dependent on the conformational status of caspase-8. These results support my previous studies, and have allowed the further refinement of our model for initiator caspase activation.