IAP proteins: sticking it to Smac

Dogma has it that suppression of the programmed cell death pathway by the IAP (inhibitor of apoptosis) proteins is achieved by their direct enzymic inhibition of the chief executioners of the apoptotic process, the caspases. In turn, the IAPs themselves can be neutralized by Smac/DIABLO (second mitochondrial activator of caspases/direct IAP binding protein with low pI), a protein which in healthy cells is thought to be sequestered in the mitochondria, but which, in response to apoptotic stimuli, is released from the mitochondria into the cytosol where it can bind to IAPs, displacing caspases and thus perpetuating the apoptotic signal. While this is an elegant and attractive model, recent studies have suggested that IAPs can also suppress apoptotic cell death independently of their ability to inhibit caspases, and two reports in this issue of the Biochemical Journal reach the interesting conclusion that the cytoprotective IAPs, ML-IAP (melanoma IAP) and ILP-2 (IAP-like protein 2), exert their effects not through direct caspase inhibition, but through the neutralization of Smac/DIABLO. The predicted outcome of these studies is a delicately controlled equilibrium between the activities of IAPs and Smac/DIABLO, leading to a dynamic regulation of the apoptotic threshold.