Reaper Is Regulated by IAP-mediated Ubiquitination

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 thre...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-02, Vol.278 (6), p.4028-4034
Main Authors: Olson, Michael R., Holley, Christopher L., Yoo, Soon Ji, Huh, Jun R., Hay, Bruce A., Kornbluth, Sally
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Base Sequence
Cells, Cultured
Cysteine Endopeptidases - metabolism
Drosophila
Drosophila Proteins - chemistry
Drosophila Proteins - genetics
Drosophila Proteins - physiology
Hydrolysis
In Situ Hybridization
Inhibitor of Apoptosis Proteins
Insect Proteins - physiology
Molecular Sequence Data
Multienzyme Complexes - metabolism
Oligonucleotides
Proteasome Endopeptidase Complex
Proteins
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Ubiquitin - metabolism
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Summary: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 inDrosophila (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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M209734200