QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 19, Issue 7, 2729-2740, July 2008

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E08-01-0107v1 19/7/2729    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cheung, H. H. Articles by Korneluk, R. G. Search for Related Content PubMed PubMed Citation Articles by Cheung, H. H. Articles by Korneluk, R. G.

The RING Domain of cIAP1 Mediates the Degradation of RING-bearing Inhibitor of Apoptosis Proteins by Distinct Pathways

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

Submitted February 1, 2008; Revised April 4, 2008; Accepted April 14, 2008
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 down-regulating 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 up-regulation. 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 -independent pathways.

* These authors contributed equally to this work.

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

Abbreviations used: BIR, baculovirus IAP repeat; cIAP1, cellular inhibitor of apoptosis 1; cIAP2, cellular inhibitor of apoptosis 2; CR, CARD-RING; DISC, death-inducing signaling complex; IAP, inhibitor of apoptosis; siRNA, small interfering RNA; Ub, ubiquitin; XIAP, X-linked IAP.