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MBC in Press, published online ahead of print April 23, 2008
Mol. Biol. Cell 10.1091/mbc.E08-01-0107

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Submitted on February 1, 2008
Revised on April 4, 2008
Accepted on April 14, 2008

The RING Domain of cIAP1 Mediates the Degradation of RING-bearing IAPs by Distinct Pathways

Herman H. Cheung,* Stéphanie Plenchette,* Chris J. Kern, Douglas J. Mahoney, and Robert G. Korneluk

Apoptosis Research Centre, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario K1H 8L1, Canada

Monitoring Editor: Kunxin Luo

The Inhibitor of Apoptosis proteins (IAPs) are key repressors of apoptosis. Several IAP proteins contain a RING domain that functions as an E3 ubiquitin ligase involved in the ubiquitin-proteasome pathway. Here we investigated the interplay of ubiquitin-proteasome pathway and RING-mediated IAP turnover. We found that the CARD-RING domain of cIAP1 (cIAP1-CR) is capable of downregulating protein levels of RING-bearing IAPs such as cIAP1, cIAP2, XIAP and Livin, while sparing NAIP and Survivin which do not possess a RING domain. To determine whether polyubiquitination was required, we tested the ability of cIAP1-CR to degrade IAPs under conditions that impair ubiquitination modifications. Remarkably, although the ablation of E1 ubiquitin-activating enzyme prevented cIAP1-CR mediated down-regulation of cIAP1 and cIAP2, there was no impact on degradation of XIAP and Livin. XIAP mutants that were not ubiquitinated in vivo were readily down-regulated by cIAP1-CR. Moreover, XIAP degradation in response to cisplatin and doxorubicin was largely prevented in cIAP1-silenced cells, despite cIAP2 upregulation. The knockdown of cIAP1 and cIAP2 partially blunted Fas ligand-mediated down-regulation of XIAP and protected cells from cell death. Together, these results show that the E3 ligase RING domain of cIAP1 targets RING-bearing IAPs for proteasomal degradation by ubiquitin-dependent and ubiquitin-independent pathways.

*These authors contributed equally to this work.

Address correspondence to: Robert G. Korneluk (bob{at}mgcheo.med.uottawa.ca)






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