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J. Biol. Chem., Vol. 279, Issue 26, 26906-26914, June 25, 2004

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Smac/Diablo Antagonizes Ubiquitin Ligase Activity of Inhibitor of Apoptosis Proteins^*

Emma M. Creagh, Brona M. Murphy, Patrick J. Duriez, Colin S. Duckett¶, and Seamus J. Martin||

From the Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland and the ^¶Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602

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.

Received for publication, December 18, 2003 , and in revised form, March 22, 2004.

^* This work was supported in part by European Union Grant QLG1-1999-00739 and Science Foundation Ireland Grant PI1/B038. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Health Research Board of Ireland fellowship.

^|| To whom correspondence should be addressed: Molecular Cell Biology Laboratory, Dept. of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland. Tel.: 353-1-608-1289; Fax: 353-1-679-8558; E-mail: martinsj{at}tcd.ie.

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