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Hid, Rpr and Grim negatively regulate DIAP1 levels through distinct mechanisms

Yoo, Soon Ji and Huh, Jun R. and Muro, Israel and Yu, Hong and Wang, Lijuan and Wang, Susan L. and Feldman, R. M. Renny and Clem, Rollie J. and Müller, H.-Arno J. and Hay, Bruce A. (2002) Hid, Rpr and Grim negatively regulate DIAP1 levels through distinct mechanisms. Nature Cell Biology, 4 (6). pp. 416-424. ISSN 1465-7392. doi:10.1038/ncb793.

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Inhibitor of apoptosis (IAP) proteins suppress apoptosis and inhibit caspases. Several IAPs also function as ubiquitin-protein ligases. Regulators of IAP auto-ubiquitination, and thus IAP levels, have yet to be identified. Here we show that Head involution defective (Hid), Reaper (Rpr) and Grim downregulate Drosophila melanogaster IAP1 (DIAP) protein levels. Hid stimulates DIAP1 polyubiquitination and degradation. In contrast to Hid, Rpr and Grim can downregulate DIAP1 through mechanisms that do not require DIAP1 function as a ubiquitin-protein ligase. Observations with Grim suggest that one mechanism by which these proteins produce a relative decrease in DIAP1 levels is to promote a general suppression of protein translation. These observations define two mechanisms through which DIAP1 ubiquitination controls cell death: first, increased ubiquitination promotes degradation directly; second, a decrease in global protein synthesis results in a differential loss of short-lived proteins such as DIAP1. Because loss of DIAP1 is sufficient to promote caspase activation, these mechanisms should promote apoptosis.

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Additional Information:© 2003 Nature Publishing Group. Received 21 January 2002; Accepted 11 March 2002; Published online 14 May 2002. Published online: 14 May 2002. We thank members of the Deshaies lab for their assistance with initial ubiquitination assays and S. Kornbluth for providing the Rpr peptide, and for sharing unpublished observations. We also thank P.D. Zamore and members of his lab for providing the Drosophila embryo translation extract and translation protocols. We also thank G.M. Rubin and E. Kwan for the production of the anti-DIAP1 monoclonal antibody and K. White for th6 flies. This work was supported in part by a grant from the Deutsche Forschungsgemeinschaft (MU1168/4-1) to H.-A.J.M. and grants from the Burroughs Wellcome Fund (New Investigator awards in the Pharmacological Sciences), the Ellison Medical Foundation, and a National Institutes of Health grant GM057422-01 to B.A.H. S.J.Y. was supported by a Jane Coffin Childs Postdoctoral fellowship. Correspondence and requests for material should be addressed to H.-A.J.M. or B.A.H.
Funding AgencyGrant Number
Deutsche Forschungsgemeinschaft (DFG)MU1168/4-1
Burroughs Wellcome FundUNSPECIFIED
Ellison Medical FoundationUNSPECIFIED
Jane Coffin Childs Postdoctoral fellowshipUNSPECIFIED
Issue or Number:6
Record Number:CaltechAUTHORS:20150408-124714784
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:56491
Deposited By: Ruth Sustaita
Deposited On:08 Apr 2015 22:42
Last Modified:10 Nov 2021 20:59

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