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XIAP inhibition of caspase-3 preserves its association with the Apaf-1 apoptosome and prevents CD95- and Bax-induced apoptosis.

Publication ,  Journal Article
Bratton, SB; Lewis, J; Butterworth, M; Duckett, CS; Cohen, GM
Published in: Cell Death Differ
September 2002

Ligation of death receptors or formation of the Apaf-1 apoptosome results in the activation of caspases and execution of apoptosis. We recently demonstrated that X-linked inhibitor-of-apoptosis protein (XIAP) associates with the apoptosome in vitro. By utilizing XIAP mutants, we now report that XIAP binds to the 'native' apoptosome complex via a specific interaction with the small p12 subunit of processed caspase-9. Indeed, we provide the first direct evidence that XIAP can simultaneously bind active caspases-9 and -3 within the same complex and that inhibition of caspase-3 by the Linker-BIR2 domain prevents disruption of BIR3-caspase-9 interactions. Recent studies suggest that inhibition of caspase-3 is dispensable for its anti-apoptotic effects. However, we clearly demonstrate that inhibition of caspase-3 is required to inhibit CD95 (Fas/Apo-1)-mediated apoptosis, whereas inhibition of either caspase-9 or caspase-3 prevents Bax-induced cell death. Finally, we illustrate for the first time that XIAP mutants, which are incapable of binding to caspases-9 and -3 are completely devoid of anti-apoptotic activity. Thus, XIAP's capacity to maintain inhibition of caspase-9 within the Apaf-1 apoptosome is influenced by its ability to simultaneously inhibit active caspase-3, and depending upon the apoptotic stimulus, inhibition of caspase-9 or 3 is essential for XIAP's anti-apoptotic activity.

Duke Scholars

Published In

Cell Death Differ

DOI

ISSN

1350-9047

Publication Date

September 2002

Volume

9

Issue

9

Start / End Page

881 / 892

Location

England

Related Subject Headings

  • fas Receptor
  • bcl-2-Associated X Protein
  • X-Linked Inhibitor of Apoptosis Protein
  • Signal Transduction
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins
  • Proteins
  • Proteasome Endopeptidase Complex
  • Mutation
  • Multienzyme Complexes
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Bratton, S. B., Lewis, J., Butterworth, M., Duckett, C. S., & Cohen, G. M. (2002). XIAP inhibition of caspase-3 preserves its association with the Apaf-1 apoptosome and prevents CD95- and Bax-induced apoptosis. Cell Death Differ, 9(9), 881–892. https://doi.org/10.1038/sj.cdd.4401069
Bratton, S. B., J. Lewis, M. Butterworth, C. S. Duckett, and G. M. Cohen. “XIAP inhibition of caspase-3 preserves its association with the Apaf-1 apoptosome and prevents CD95- and Bax-induced apoptosis.Cell Death Differ 9, no. 9 (September 2002): 881–92. https://doi.org/10.1038/sj.cdd.4401069.
Bratton SB, Lewis J, Butterworth M, Duckett CS, Cohen GM. XIAP inhibition of caspase-3 preserves its association with the Apaf-1 apoptosome and prevents CD95- and Bax-induced apoptosis. Cell Death Differ. 2002 Sep;9(9):881–92.
Bratton, S. B., et al. “XIAP inhibition of caspase-3 preserves its association with the Apaf-1 apoptosome and prevents CD95- and Bax-induced apoptosis.Cell Death Differ, vol. 9, no. 9, Sept. 2002, pp. 881–92. Pubmed, doi:10.1038/sj.cdd.4401069.
Bratton SB, Lewis J, Butterworth M, Duckett CS, Cohen GM. XIAP inhibition of caspase-3 preserves its association with the Apaf-1 apoptosome and prevents CD95- and Bax-induced apoptosis. Cell Death Differ. 2002 Sep;9(9):881–892.

Published In

Cell Death Differ

DOI

ISSN

1350-9047

Publication Date

September 2002

Volume

9

Issue

9

Start / End Page

881 / 892

Location

England

Related Subject Headings

  • fas Receptor
  • bcl-2-Associated X Protein
  • X-Linked Inhibitor of Apoptosis Protein
  • Signal Transduction
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins
  • Proteins
  • Proteasome Endopeptidase Complex
  • Mutation
  • Multienzyme Complexes