Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases

Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct... Several human inhibitor of apoptosis (IAP) family proteins function by directly inhibiting specific caspases in a mechanism that does not require IAP cleavage. In this study, however, we demonstrate that endogenous XIAP is cleaved into two fragments during apoptosis induced by the tumor necrosis factor family member Fas (CD95). The two fragments produced comprise the baculoviral inhibitory repeat (BIR) 1 and 2 domains (BIR1‐2) and the BIR3 and RING (BIR3‐Ring) domains of XIAP. Overexpression of the BIR1‐2 fragment inhibits Fas‐induced apoptosis, albeit at significantly reduced efficiency compared with full‐length XIAP. In contrast, overexpression of the BIR3‐Ring fragment results in a slight enhancement of Fas‐directed apoptosis. Thus, cleavage of XIAP may be one mechanism by which cell death programs circumvent the anti‐apoptotic barrier posed by XIAP. Interestingly, ectopic expression of the BIR3‐Ring fragment resulted in nearly complete protection from Bax‐induced apoptosis. Use of purified recombinant proteins revealed that BIR3‐Ring is a specific inhibitor of caspase‐9 whereas BIR1‐2 is specific for caspases 3 and 7. Therefore XIAP possesses two different caspase inhibitory activities which can be attributed to distinct domains within XIAP. These data may provide an explanation for why IAPs have evolved with multiple BIR domains. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The EMBO Journal Wiley

Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases

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Publisher
Wiley
Copyright
Copyright © 2013 Wiley Periodicals, Inc
ISSN
0261-4189
eISSN
1460-2075
DOI
10.1093/emboj/18.19.5242
Publisher site
See Article on Publisher Site

Abstract

Several human inhibitor of apoptosis (IAP) family proteins function by directly inhibiting specific caspases in a mechanism that does not require IAP cleavage. In this study, however, we demonstrate that endogenous XIAP is cleaved into two fragments during apoptosis induced by the tumor necrosis factor family member Fas (CD95). The two fragments produced comprise the baculoviral inhibitory repeat (BIR) 1 and 2 domains (BIR1‐2) and the BIR3 and RING (BIR3‐Ring) domains of XIAP. Overexpression of the BIR1‐2 fragment inhibits Fas‐induced apoptosis, albeit at significantly reduced efficiency compared with full‐length XIAP. In contrast, overexpression of the BIR3‐Ring fragment results in a slight enhancement of Fas‐directed apoptosis. Thus, cleavage of XIAP may be one mechanism by which cell death programs circumvent the anti‐apoptotic barrier posed by XIAP. Interestingly, ectopic expression of the BIR3‐Ring fragment resulted in nearly complete protection from Bax‐induced apoptosis. Use of purified recombinant proteins revealed that BIR3‐Ring is a specific inhibitor of caspase‐9 whereas BIR1‐2 is specific for caspases 3 and 7. Therefore XIAP possesses two different caspase inhibitory activities which can be attributed to distinct domains within XIAP. These data may provide an explanation for why IAPs have evolved with multiple BIR domains.

Journal

The EMBO JournalWiley

Published: Jan 1, 1999

Keywords: ; ;

References

  • IAPs block apoptotic events induced by caspase‐8 and cytochrome c by direct inhibition of distinct caspases
    Deveraux, QL; Roy, N; Stennicke, HR; Van Arsdale, T; Zhou, Q; Srinivasula, M; Alnemri, ES; Salvesen, GS; Reed, JC
  • Mechanisms of CD95 (APO‐1/Fas)‐mediated apoptosis
    Peter, ME; Krammer, PH
  • 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
  • Two CD95 (APO‐1/Fas) signaling pathways
    Scaffidi, C; Fulda, S; Srinivasan, A; Friesen, C; Li, F; Tomaselli, KJ; Debatin, KM; Krammer, PH; Peter, ME
  • Properties of the caspases
    Stennicke, HR; Salvesen, GS

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