Regulation of the Drosophila Apoptosome through Feedback Inhibition

Apoptosis is induced by caspases, which are members of the cysteine protease family 1. 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 apoptosome 2,3. Activated initiator caspases subsequently cleave and activate effector caspases. While 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 migration 4. Here we show that the Drosophila apoptosome engages in a feedback inhibitory loop, thereby moderating 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 upon Dronc’s catalytic site 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.