The activation of caspases — which are essential effectors of apoptosis — is regulated by IAP ('inhibitor of apoptosis') proteins. In Drosophila, cell death and caspase activation require proteins of the Reaper, Hid, Grim and Sickle family (referred to here as RHG proteins). A series of reports published in Nature Cell Biology now sheds light on the relationship between these essential components of the apoptotic pathway.
The reports show that regulation of the levels of DIAP1 (Drosophila IAP1) is important for the initiation of apoptosis by RHG proteins in vivo. All six groups saw that RHG proteins reduce DIAP1 levels. In mammals, it has been reported that IAPs can be degraded by the proteasome after treatment with an apoptotic stimulus. Also, the RING-finger domain of IAPs has E3 ligase activity, which allows the polymerization of polyubiquitin chains on target proteins, and thereby targets them for degradation by the proteasome.
So, each group checked whether RHG proteins could induce ubiquitylation of DIAP1 and its degradation by the proteasome. They found that RHG proteins can indeed induce the autoubiquitylation of DIAP1 and its degradation in a proteasome-dependent manner. This requires the presence of the RING-finger domain of DIAP1, which is also essential for RHG-induced killing.
Ubiquitylation of a protein substrate requires three successive enzymatic reactions that are controlled by an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme and an E3 ubiquitin protein ligase. As mentioned before, DIAP1 has E3-ligase activity, and Hermann Steller's group identified an E2 enzyme, UBCD1, that is required for Reaper- and Grim-induced DIAP1 ubiquitylation and degradation, and for Reaper- and Grim-induced killing. The groups of Ross Cagan and John Nambu identified another protein, Morgue, that is required for the ubiquitin-conjugating reaction. Morgue is related to E2 enzymes, yet lacks the consensus active site, so it could work in association with another E2 enzyme. John Nambu's lab provides preliminary evidence that it might bind SkpA, a component of the SCF–E3 ubiquitin ligase complex.
Sally Kornbluth and Bruce Hay made another interesting observation: they saw that RHG proteins could reduce levels of general protein translation, which would contribute further to reducing DIAP1 levels. And finally, Pascal Meier's lab found that DIAP1 also induces the ubiquitylation of the Drosophila caspase Dronc and its inactivation. It will be interesting to establish how DIAP1-mediated ubiquitylation of Dronc leads to its inactivation, as the authors have preliminary evidence is that this does not occur by proteasome degradation.
These findings put RHG protein signalling into a new perspective, but they also raise many questions about the link between Morgue and E3 ligase complexes, and about the mechanism by which RHG proteins regulate translation.
ORIGINAL RESEARCH PAPER
Yoo, S. J. et al. Hid, Rpr and Grim negatively regulate DIAP1 levels through distinct mechanisms. Nature Cell Biol. 4, 416–424 (2002)
Hays, R., Wickline, L. & Cagan, R. Morgue mediates apoptosis in the Drosophila melanogaster retina by promoting degradation of DIAP1. Nature Cell Biol. 4, 425–431 (2002)
Ryoo, H. D. et al. Regulation of Drosophila IAP1 degradation and apoptosis by Reaper and UBCD1. Nature Cell Biol. 4, 432–438 (2002)
S Holley, C. L., Olson, M. R., Colón-Ramos, D. A. & Kornbluth, S. Reaper eliminates IAP proteins through stimulated IAP degradation and generalized translational inhibition. Nature Cell Biol. 4, 439–444 (2002)
Wilson, R. et al. The DIAP1 RING finger mediates ubiquitination of Dronc and is indispensable for regulating apoptosis. Nature Cell Biol. 4, 445–450 (2002)
Wing, J. et al. Drosophila Morgue is an F box/ubiquitin conjugase domain protein important for grim-reaper mediated apoptosis. Nature Cell Biol. 4, 451–456 (2002)
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Ferrier, V. Getting rid of obstacles. Nat Rev Mol Cell Biol 3, 398 (2002). https://doi.org/10.1038/nrm845
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DOI: https://doi.org/10.1038/nrm845