Letter abstract

Nature Cell Biology 10, 1440 - 1446 (2008)
Published online: 16 November 2008 | doi:10.1038/ncb1803

Regulation of the Drosophila apoptosome through feedback inhibition

Peter J. Shapiro1,2, Hans H. Hsu1,2, Heekyung Jung1,2, Edith S. Robbins1 & Hyung Don Ryoo1


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.

  1. Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
  2. These authors contributed equally.

Correspondence to: Hyung Don Ryoo1 e-mail: hyungdon.ryoo@nyumc.org


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