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Drosophila Morgue is an F box/ubiquitin conjugase domain protein important for grim-reaper mediated apoptosis

Nature Cell Biology volume 4, pages 451–456 (2002)Cite this article

Abstract

In Drosophila melanogaster, apoptosis is controlled by the integrated actions of the Grim-Reaper (Grim-Rpr) and Drosophila Inhibitor of Apoptosis (DIAP) proteins (reviewed in refs 1–4). The anti-apoptotic DIAPs bind to caspases and inhibit their proteolytic activities. DIAPs also bind to Grim-Rpr proteins, an interaction that promotes caspase activity and the initiation of apoptosis. Using a genetic modifier screen, we identified four enhancers of grim-reaper-induced apoptosis that all regulate ubiquitination processes: uba-1, skpA, fat facets (faf), and morgue. Strikingly, morgue encodes a unique protein that contains both an F box and a ubiquitin E2 conjugase domain that lacks the active site Cys required for ubiquitin linkage. A reduction of morgue activity suppressed grim-reaper-induced cell death in Drosophila. In cultured cells, Morgue induced apoptosis that was suppressed by DIAP1. Targeted morgue expression downregulated DIAP1 levels in Drosophila tissue, and Morgue and Rpr together downregulated DIAP1 levels in cultured cells. Consistent with potential substrate binding functions in an SCF ubiquitin E3 ligase complex, Morgue exhibited F box-dependent association with SkpA and F box-independent association with DIAP1. Morgue may thus have a key function in apoptosis by targeting DIAP1 for ubiquitination and turnover.

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Figure 1: Ubiquitin pathway genes are genetic modifiers of grim-rpr-induced eye cell death.
Figure 2: Organization and expression of the morgue gene.
Figure 3: morgue function is important for grim-rpr-mediated cell death.
Figure 4: Morgue associates with SkpA and DIAP1, and negatively influences DIAP1 levels.

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Acknowledgements

The authors are grateful to S. Boulton for providing a SkpA expression plasmid and purified GST–SkpA protein. We also thank the Bloomington Drosophila Stock Center, G. Reuter, J. Szidonya, the Berkeley Drosophila Genome Project and the Developmental Studies Hybridoma Bank for providing fly strains, DNAs and antibodies. We are grateful to R. Cagan for discussions on morgue gene analyses before publication. K.W. is supported by National Institutes of Health grant GM55568 and a grant from the Shiseido Company of Japan to the Massachusetts General Hospital/Harvard Medical School. L.M.S. and J.R.N. were supported by NIH grant AG55118.

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Author notes

  1. John P. Wing

    Present address: Phylos Inc., Lexington, MA 02421, USA

  2. Paul S. Andrews

    Present address: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 7599, USA

Authors and Affiliations

  1. Biology Department, University of Massachusetts at Amherst, Amherst, 01003, MA, USA

    John P. Wing, Barbara A. Schreader, Yiqin Wang, Paul S. Andrews, Carolyn K. Dong, Justyne L. Ogdahl, Lawrence M. Schwartz, Kristin White & John R. Nambu

  2. Program in Molecular and Cellular Biology, University of Massachusetts at Amherst, Amherst, 01003, MA, USA

    John P. Wing, Barbara A. Schreader, Yiqin Wang, Lawrence M. Schwartz & John R. Nambu

  3. Cutaneous Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Building 149, 13th Street, Charlestown, 02129, MA, USA

    Takakazu Yokokura, Neda Huseinovic & Kristin White

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Correspondence to John R. Nambu.

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Supplementary information

Supplementary figure and table

Figure S1. morgue expression induces apoptosis in cultured Spodoptera Sf-9 cells. (PDF 67 kb)

Table 1. Modification of R/Grim-induced Eye Cell Death by EP Insertions

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Wing, J., Schreader, B., Yokokura, T. et al. Drosophila Morgue is an F box/ubiquitin conjugase domain protein important for grim-reaper mediated apoptosis. Nat Cell Biol 4, 451–456 (2002). https://doi.org/10.1038/ncb800

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