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Regulation of the Drosophila apoptosome through feedback inhibition

Nature Cell Biology volume 10, pages 1440–1446 (2008)Cite this article

Abstract

Apoptosis is induced by caspases, which are members of the cysteine protease family1. Caspases are synthesized as inactive zymogens and initiator caspases first gain activity by associating with an oligomeric complex of their adaptor proteins, such as the apoptosome2,3. Activated initiator caspases subsequently cleave and activate effector caspases. Although such a proteolytic cascade would predict that a small number of active caspases could irreversibly amplify caspase activity and trigger apoptosis, many cells can maintain moderate levels of caspase activity to perform non-apoptotic roles in cellular differentiation, shape change and migration4. Here we show that the Drosophila melanogaster apoptosome engages in a feedback inhibitory loop, which moderates its activation level in vivo. Specifically, the adaptor protein Apaf-1 lowers the level of its associated initiator caspase Dronc, without triggering apoptosis. Conversely, Dronc lowers Apaf-1 protein levels. This mutual suppression depends on the catalytic site of Dronc and a caspase cleavage site within Apaf-1. Moreover, the Drosophila inhibitor of apoptosis protein 1 (Diap1) is required for this process. We speculate that this feedback inhibition allows cells to regulate the degree of caspase activation for apoptotic and non-apoptotic purposes.

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Figure 1: Apaf-1 lowers Dronc protein levels in Drosophila tissues.
Figure 2: Overexpression of Apaf-1 and Dronc in eye imaginal discs.
Figure 3: The mutually suppressive relationship between Dronc and Apaf-1 requires Dronc function.
Figure 4: Dronc cleaves Apaf-1 through a caspase cleavage site.
Figure 5: Diap1 prevents Apaf-1 and Dronc from accumulating together in cells.

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Acknowledgements

We thank John Abrams, Andreas Bergmann, George Jackson, Pascal Meier for fly stocks; David Sabatini for making available the scanning electron microscope; Milton Adesnik, Ramanuj Dasgupta, Zehra Ordulu, David Sabatini, Greg Suh and Jessica Treisman for advice and comments on the manuscript. P.J.S. is supported by an NIH predoctoral training grant 5T32GM007239-32. H.D.R. is a Special Fellow of the Leukemia-Lymphoma Society, a Basil O'Conner Scholar of the March of Dimes Foundation and an Ellison Medical Foundation New Scholar. This work was supported by a grant to H.D.R. from the National Institutes of Health (1RO1GM079425)

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  1. Peter J. Shapiro, Hans H. Hsu and Heekyung Jung: These authors contributed equally.

Authors and Affiliations

  1. Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, 10016, NY, USA

    Peter J. Shapiro, Hans H. Hsu, Heekyung Jung, Edith S. Robbins & Hyung Don Ryoo

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Contributions

H.D.R. conceived the project; P.J.S., H.J. and H.D.R. designed the experiments and analysed the data; all authors performed experiments; E.S.R. contributed to the scanning electron microscopy experiments; H.D.R. wrote the paper and all authors read and edited the manuscript.

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Correspondence to Hyung Don Ryoo.

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Shapiro, P., Hsu, H., Jung, H. et al. Regulation of the Drosophila apoptosome through feedback inhibition. Nat Cell Biol 10, 1440–1446 (2008). https://doi.org/10.1038/ncb1803

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