Inhibiting the Inhibitor

Science's STKE  11 Jul 2000:
Vol. 2000, Issue 40, pp. tw6
DOI: 10.1126/stke.2000.40.tw6

One major apoptosis pathway involves the release of cytochrome c from mitochondrial membranes and the subsequent activation of caspases. Inhibitors of apoptosis proteins (IAPs) shut down this pathway by binding to and inhibiting the caspases. Although Drosophila proteins have been identified that counteract the anti-apoptotic activity of IAPs, the functional equivalents in mammalian cells have remained elusive. Now, two groups have identified a human protein called Smac or DIABLO that opposes the inhibitory activity of IAPs. Du et al. and Verhagen et al. both show that this protein, like cytochrome c, is located in mitochondrial membranes and is released into the cytosol when cells undergo apoptosis. The protein is ubiquitously expressed in human tissue and appears to associate with IAPS. Smac/DIABLO has a mitochondrial targeting sequence that is cleaved in the mature form of the protein and it is the mature form that predominantly associates with IAPs. Expression of Smac/DIABLO also interfered with the protective effects of IAPs in cells exposed to UV radiation. The groups speculate that release of Smac/DIABLO from mitochondria could be regulated by the Bcl-2 family of proteins and that association with IAPs may prevent IAP binding to caspases.

Du, C., Fang, M., Li, Y., Li, L., and Wang, X. (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102: 33-42. [Online Journal]

Verhagen, A.M., Ekert, P.G., Pakusch, M., Silke, J., Connolly, L.M., Reid, G.E., Moritz, R.L., Simpson, R.J., and Vaux, D.L. (2000) Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102: 43053. [Online Journal]