The membrane-associated inhibitor of apoptosis protein, BRUCE/Apollon, antagonizes both the precursor and mature forms of Smac and caspase-9.
Smac/DIABLO, HtrA2/Omi, and caspase-9 play key roles in the initiation of apoptosis. The inhibitor of apoptosis proteins (IAPs) are believed to bind to the N-terminal IAP binding motifs of the mature (proteolytically processed) forms of Smac, HtrA2, and caspase-9. However, we show here that BRUCE/Apollon, a 528-kDa IAP whose degradation promotes apoptosis, associates with their precursors as well as the mature forms by binding to regions in addition to the IAP binding motif. Through these associations, BRUCE promotes the degradation of Smac and inhibits the activity of caspase-9 but not the effector caspase, caspase-3. In response to apoptotic stimuli, BRUCE is degraded by proteasomes and/or cleaved by caspases and HtrA2 depending on the specific stimulus and the cell type. These results suggest that the ability of BRUCE to antagonize both the precursor and mature forms of Smac and caspase-9 is an important mechanism for the prevention of apoptosis under normal conditions.
Qiu
Xiao-Bo
XB
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Goldberg
Alfred L
AL
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics; D002461:Cell Line, Transformed; D005786:Gene Expression Regulation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000235:genetics; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; C401541:BIRC6 protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D011498:Protein Precursors; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases