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Regulation of Drosophila IAP1 degradation and apoptosis by reaper and ubcD1

Nature Cell Biology volume 4, pages 432–438 (2002)Cite this article

An Erratum to this article was published on 01 July 2002

Abstract

Cell death in higher organisms is negatively regulated by Inhibitor of Apoptosis Proteins (IAPs), which contain a ubiquitin ligase motif, but how ubiquitin-mediated protein degradation is regulated during apoptosis is poorly understood. Here, we report that Drosophila melanogaster IAP1 (DIAP1) auto-ubiquitination and degradation is actively regulated by Reaper (Rpr) and UBCD1. We show that Rpr, but not Hid (head involution defective), promotes significant DIAP1 degradation. Rpr-mediated DIAP1 degradation requires an intact DIAP1 RING domain. Among the mutations affecting ubiquitination, we found ubcD1, which suppresses rpr-induced apoptosis. UBCD1 and Rpr specifically bind to DIAP1 and stimulate DIAP1 auto-ubiquitination in vitro. Our results identify a novel function of Rpr in stimulating DIAP1 auto-ubiquitination through UBCD1, thereby promoting its degradation.

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Figure 1: Expression of DIAP1 protein and diap1 enhancer trap in wing imaginal discs.
Figure 2: rpr induces post-transcriptional downregulation of DIAP1.
Figure 3: rpr induced DIAP1 degradation is dependent on the RING domain.
Figure 4: Mutation in ubcD1 dominantly suppresses cell killing induced by GMR-hid, GMR-rpr and GMR-diap1-RING.
Figure 5: Rpr and UBCD1 bind DIAP1 and promote DIAP1 auto-ubiquitination in vitro.
Figure 6: DIAP1 levels increase in ubcD1−/− clones.
Figure 7: ubcD1−/− adults have extra-sensory neurons (macrochaetes) in the scutellum.

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Acknowledgements

We are grateful to M. Gatti, J. Fischer, B. Hay, S. Jentsch, P. Meier, B. Mignotte, G. Rubin and the Bloomington stock centre for providing stocks and reagents. We thank the Steller lab members for advice and criticism, R. Cagan and P. Meier for sharing results before publication, S. Shaham, S. Sampath and B. Mollereau for critically reading the manuscript, and R. Cisse and T. Gorenc for technical assistance. H.D.R. is a fellow of the Leukemia-Lymphoma Society. A.B. is supported by The Robert A. Welch Foundation, the MD Anderson Research Trust and the Bush Endowment for innovative Cancer Research. H.S. is an Investigator of the Howard Hughes Medical Institute. Part of this work was supported by National Institutes of Health grant RO1GM60124 and The Lady Davis Fellowship from the Technion Medical Faculty in Israel to H.S.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Strang Laboratory of Cancer Research, The Rockefeller University, Box 252, 1230 York Ave., New York, 10021, NY, USA

    Hyung Don Ryoo & Hermann Steller

  2. Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, 77030, TX, USA

    Andreas Bergmann

  3. Department of Biochemistry, Faculty of Medicine, Technion, 31096, Haifa, Israel

    Hedva Gonen & Aaron Ciechanover

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Ryoo, H., Bergmann, A., Gonen, H. et al. Regulation of Drosophila IAP1 degradation and apoptosis by reaper and ubcD1. Nat Cell Biol 4, 432–438 (2002). https://doi.org/10.1038/ncb795

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