IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases.
Inhibitor of apoptosis (IAP) gene products play an evolutionarily conserved role in regulating programmed cell death in diverse species ranging from insects to humans. Human XIAP, cIAP1 and cIAP2 are direct inhibitors of at least two members of the caspase family of cell death proteases: caspase-3 and caspase-7. Here we compared the mechanism by which IAPs interfere with activation of caspase-3 and other effector caspases in cytosolic extracts where caspase activation was initiated by caspase-8, a proximal protease activated by ligation of TNF-family receptors, or by cytochrome c, which is released from mitochondria into the cytosol during apoptosis. These studies demonstrate that XIAP, cIAP1 and cIAP2 can prevent the proteolytic processing of pro-caspases -3, -6 and -7 by blocking the cytochrome c-induced activation of pro-caspase-9. In contrast, these IAP family proteins did not prevent caspase-8-induced proteolytic activation of pro-caspase-3; however, they subsequently inhibited active caspase-3 directly, thus blocking downstream apoptotic events such as further activation of caspases. These findings demonstrate that IAPs can suppress different apoptotic pathways by inhibiting distinct caspases and identify pro-caspase-9 as a new target for IAP-mediated inhibition of apoptosis.
Deveraux
Q L
QL
The Burnham Institute, Program on Apoptosis and Cell Death Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Roy
N
N
Stennicke
H R
HR
Van Arsdale
T
T
Zhou
Q
Q
Srinivasula
S M
SM
Alnemri
E S
ES
Salvesen
G S
GS
Reed
J C
JC
D017209:Apoptosis; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D002457:Cell Extracts; D002461:Cell Line, Transformed; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism*; D003600:Cytosol; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein
D002457:Cell Extracts; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D004792:Enzyme Precursors; D051034:Inhibitor of Apoptosis Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C494833:BIRC2 protein, human; D044767:Ubiquitin-Protein Ligases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases