Smac/Diablo antagonizes ubiquitin ligase activity of inhibitor of apoptosis proteins

Creagh, Emma M., Murphy, Brona M., Duriez, Patrick J., Duckett, Colin S. and Martin, Seamus J. (2004) Smac/Diablo antagonizes ubiquitin ligase activity of inhibitor of apoptosis proteins. The Journal of Biological Chemistry, 279 (26), 26906-26914. (doi:10.1074/jbc.M313859200). (PMID:15078891)

Abstract

Inhibitor of apoptosis proteins (IAPs) can block apoptosis through binding to active caspases and antagonizing their function. IAP function can be neutralized by Smac/Diablo, an IAP-binding protein that is released from mitochondria during apoptosis. In addition to their ability to interact with caspases, certain IAPs also display ubiquitin-protein isopeptide ligase activity because of the presence of a RING domain. However, it is not known whether the ubiquitin-protein isopeptide ligase activities of human IAPs contribute to their apoptosis inhibitory activity or whether this IAP property can be modulated through association with Smac/Diablo. Here we demonstrate that the ubiquitin ligase activities of XIAP, and to a lesser extent c-IAP-1 and c-IAP2, are potently repressed through binding to Smac/Diablo. We also show that mutation of the XIAP RING domain rendered this IAP a less effective inhibitor of apoptosis, suggesting that the ubiquitin ligase activity of XIAP contributes to its anti-apoptotic function. These data suggest that Smac/Diablo potentiates apoptosis by simultaneously antagonizing caspase-IAP interactions and repressing IAP ubiquitin ligase activities

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