Unrestrained caspase-dependent cell death caused by loss of Diap1 function requires the Drosophila Apaf-1 homolog, Dark.
In mammals and Drosophila, apoptotic caspases are under positive control via the CED-4/Apaf-1/Dark adaptors and negative control via IAPs (inhibitor of apoptosis proteins). However, the in vivo genetic relationship between these opposing regulators is not known. In this study, we demonstrate that a dark mutation reverses catastrophic defects seen in Diap1 mutants and rescues cells specified for Diap1- regulated cell death in development and in response to genotoxic stress. We also find that dark function is required for hyperactivation of caspases which occurs in the absence of Diap1. Since the action of dark is epistatic to that of Diap1, these findings demonstrate that caspase-dependent cell death requires concurrent positive input through Apaf-1-like proteins together with disruption of IAP-caspase complexes.
Rodriguez
Antony
A
Department of Cell Biology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9039, USA.
Chen
Po
P
Oliver
Holt
H
Abrams
John M
JM
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1; D020169:Caspases / Q000502:physiology*; D002490:Central Nervous System; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000502:physiology; D029721:Drosophila Proteins; D004843:Epistasis, Genetic; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins / Q000235:genetics / Q000502:physiology*; D009479:Neuropeptides / Q000502:physiology; D010455:Peptides / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000502:physiology*
D053477:Apoptotic Protease-Activating Factor 1; C111891:DIAP1 protein, Drosophila; D029721:Drosophila Proteins; C108880:HID protein, Drosophila; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins; D009479:Neuropeptides; D010455:Peptides; D011506:Proteins; C400550:dark protein, Drosophila; C108881:grim protein, Drosophila; C086973:rpr protein, Drosophila; D020169:Caspases