Smac, a mitochondrial protein that promotes cytochrome c-dependent caspaseactivation by eliminating IAP inhibition

We report here the identification of a novel protein, Smac, which promotes caspase activation in the cytochrome c/Apaf-1/caspase-9 pathway. Smac promo tes caspase-9 activation by binding to inhibitor of apoptosis proteins, IAP s, and removing their inhibitory activity. Smac is normally a mitochondrial protein but is released into the cytosol when cells undergo apoptosis. Mit ochondrial import and cleavage of its signal peptide are required for Smac to gain its apoptotic activity. Overexpression of Smac increases cells' sen sitivity to apoptotic stimuli. Smac is the second mitochondrial protein, al ong with cytochrome c, that promotes apoptosis by activating caspases.