IAPs block apoptotic events induced by caspase‐8 and cytochrome c by direct inhibition of distinct caspases

IAPs block apoptotic events induced by caspase‐8 and cytochrome c by direct inhibition of... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The EMBO Journal Wiley

IAPs block apoptotic events induced by caspase‐8 and cytochrome c by direct inhibition of distinct caspases

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Publisher
Wiley
Copyright
Copyright © 2013 Wiley Periodicals, Inc
ISSN
0261-4189
eISSN
1460-2075
D.O.I.
10.1093/emboj/17.8.2215
Publisher site
See Article on Publisher Site

Abstract

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.

Journal

The EMBO JournalWiley

Published: Mar 15, 1999

Keywords: ; ; ;

References

  • Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD‐specific caspase activation and independently of mitochondrial transmembrane depolarization
    Bossy‐Wetzel, E; Newmeyer, D; Green, D
  • The c‐IAP‐1 and c‐IaP‐2 proteins are direct inhibitors of specific caspases
    Roy, N; Deveraux, QL; Takashashi, R; Salvesen, GS; Reed, JC

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