Regulation of the Drosophila apoptosome through feedback inhibition.
Apoptosis is induced by caspases, which are members of the cysteine protease family. 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. 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 migration. 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.
Shapiro
Peter J
PJ
Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
Hsu
Hans H
HH
Jung
Heekyung
H
Robbins
Edith S
ES
Ryoo
Hyung Don
HD
D000818:Animals; D053478:Apoptosomes / Q000378:metabolism* / Q000648:ultrastructure; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D005123:Eye / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D025461:Feedback, Physiological; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism
D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1; C111891:DIAP1 protein, Drosophila; D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D020169:Caspases; C118731:dronc protein, Drosophila