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Reaper is regulated by UP-mediated ubiquitination

Olson, Michael R. and Holley, Christopher L. and Yoo, Soon Ji and Huh, Jun R. and Hay, Bruce A. and Kornbluth, Sally (2003) Reaper is regulated by UP-mediated ubiquitination. Journal of Biological Chemistry, 278 (6). pp. 4028-4034. ISSN 0021-9258. http://resolver.caltech.edu/CaltechAUTHORS:OLSjbc03

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Abstract

In most cases, apoptotic cell death culminates in the activation of the caspase family of cysteine proteases, leading to the orderly dismantling and elimination of the cell. The IAPs (inhibitors of apoptosis) comprise a family of proteins that oppose caspases and thus act to raise the apoptotic threshold. Disruption of IAP-mediated caspase inhibition has been shown to be an important activity for pro-apoptotic proteins in Drosophila (Reaper, HID, and Grim) and in mammalian cells (Smac/DIABLO and Omi/HtrA2). In addition, in the case of the fly, these proteins are able to stimulate the ubiquitination and degradation of IAPs by a mechanism involving the ubiquitin ligase activity of the IAP itself. In this report, we show that the Drosophila RHG proteins (Reaper, HID, and Grim) are themselves substrates for IAP-mediated ubiquitination. This ubiquitination of Reaper requires IAP ubiquitin-ligase activity and a stable interaction between Reaper and the IAP. Additionally, degradation of Reaper can be blocked by mutating its potential ubiquitination sites. Most importantly, we also show that regulation of Reaper by ubiquitination is a significant factor in determining its biological activity. These data demonstrate a novel function for IAPs and suggest that IAPs and Reaper-like proteins mutually control each other's abundance.


Item Type:Article
Additional Information:© 2003 by The American Society for Biochemistry and Molecular Biology, Inc. Received for publication, September 23, 2002, and in revised form, November 19, 2002. Published, JBC Papers in Press, November 20, 2002. We thank Dr. Kristin White (Harvard/MGH) for providing the pIE3/DIAP1 clone. We are grateful to Dr. Rick Fehon and Rima Kulikauskas for assistance and space for insect cell culture.
Subject Keywords:PROGRAMMED CELL-DEATH; STRUCTURAL BASIS; DROSOPHILA REAPER; MAMMALIAN-CELLS; PROTEIN LIGASE; APOPTOSIS; GRIM; XIAP; INHIBITION; SYSTEM
Record Number:CaltechAUTHORS:OLSjbc03
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:OLSjbc03
Alternative URL:http://dx.doi.org/10.1074/jbc.M209734200
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:4375
Collection:CaltechAUTHORS
Deposited By: Lindsay Cleary
Deposited On:18 Aug 2006
Last Modified:26 Dec 2012 08:59

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