Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

XIAP, the guardian angel

Nature Reviews Molecular Cell Biology volume 2, pages 550–556 (2001)Cite this article

Abstract

Controlling the activity of caspases is essential for the appropriate execution of cell death and the regulation of cell survival. One cellular inhibitor of apoptosis, XIAP, has emerged as a crucial regulator of caspases, and is itself subject to complex negative regulation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: XIAP is a modular protein.
Figure 2: BIR3 domain of XIAP binds cleaved caspase-9.
Figure 3: XIAP associates with the apoptosome.
Figure 4: Proposed model for the centrality of XIAP in caspase regulation.

Similar content being viewed by others

References

  1. Nicholson, D. W. Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ. 6, 1028–1042 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Holcik, M., Gibson, H. & Korneluk, R. G. XIAP: Apoptotic brake and promising therapeutic target. Apoptosis 6, 251–259 (2001).

    Article  Google Scholar 

  3. Takahashi, R. et al. A single BIR domain of XIAP is sufficient for inhibiting caspases. J. Biol. Chem. 273, 7787–7790 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Deveraux, Q. L. & Reed, J. C. IAP family proteins — suppressors of apoptosis. Genes Dev. 13, 239–252 (1999).

    CAS  PubMed  Google Scholar 

  5. Sun, C. et al. NMR structure and mutagenesis of the third BIR domain of the inhibitor of apoptosis protein XIAP. J. Biol. Chem. 275, 33777–33781 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Srinivasula, S. M. et al. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature 410, 112–116 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Riedl, S. J. et al. Structural basis for the inhibition of caspase-3 by XIAP. Cell 104, 791–800 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Huang, Y. et al. Structural basis of caspase inhibition by XIAP. Differential roles of the linker versus the BIR domain. Cell 104, 781–790 (2001).

    CAS  PubMed  Google Scholar 

  9. Chai, J. et al. Structural basis of caspase-7 inhibition by XIAP. Cell 104, 769–780 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Roy, N., Deveraux, Q. L., Takahashi, R., Salvesen, G. S. & Reed, J. C. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J. 16, 6914–6925 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Deveraux, Q. L. et al. Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases. EMBO J. 18, 5242–5251 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bratton, S. B. et al. Recruitment, activation and retention of caspases-9 and -3 by Apaf-1 apoptosome and associated XIAP complexes. EMBO J. 20, 998–1009 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zeuner, A., Eramo, A., Peschle, C. & De Maria, R. Caspase activation without death. Cell Death Differ. 6, 1075–1080 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Zhou, Q. et al. Interaction of the baculovirus anti-apoptotic protein p35 with caspases. Specificity, kinetics, and characterization of the caspase/p35 complex. Biochemistry 37, 10757–10765 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Xu, G. et al. Covalent inhibition revealed by the crystal structure of the caspase-8/p35 complex. Nature 410, 494–497 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Du, C., Fang, M., Li, Y., Li, L. & Wang, X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102, 33–42 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Verhagen, A. M. et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102, 43–53 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Chai, J. et al. Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature 406, 855–862 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Wu, G. et al. Structural basis of IAP recognition by Smac/DIABLO. Nature 408, 1008–1012 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Liu, Z. et al. Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature 408, 1004–1008 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Bangs, P. & White, K. Regulation and execution of apoptosis during Drosophila development. Dev. Dyn. 218, 68–79 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Srinivasula, S. M. et al. Molecular determinants of the caspase-promoting activity of Smac/DIABLO and its role in the death receptor pathway. J. Biol. Chem. 275, 36152–36157 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Roberts, D. L., Merrison, W., MacFarlane, M. & Cohen, G. M. The inhibitor of apoptosis protein-binding domain of Smac is not essential for its proapoptotic activity. J. Cell Biol. 153, 221–228 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liston, P. et al. Identification of XAF1 as an antagonist of XIAP anti-caspase activity. Nature Cell Biol. 3, 128–133 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Lazebnik, Y. A. et al. Studies of the lamin proteinase reveal multiple parallel biochemical pathways during apoptotic execution. Proc. Natl Acad. Sci. USA 92, 9042–9046 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Takahashi, A. et al. Cleavage of lamin A by Mch2α but not CPP32: multiple interleukin 1β-converting enzyme-related proteases with distinct substrate recognition properties are active in apoptosis. Proc. Natl Acad. Sci. USA 93, 8395–8400 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Faleiro, L. & Lazebnik, Y. Caspases disrupt the nuclear–cytoplasmic barrier. J. Cell Biol. 151, 951–959 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Levkau, B. et al. XIAP induces cell-cycle arrest and activates nuclear factor-κB: new survival pathways disabled by caspase-mediated cleavage during apoptosis of human endothelial cells. Circ. Res. 88, 282–290 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Harlin, H., Reffey, S. B., Duckett, C. S., Lindsten, T. & Thompson, C. B. Characterization of XIAP-deficient mice. Mol. Cell. Biol. 21, 3604–3608 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fong, W. G. et al. Expression and genetic analysis of XIAP-associated Factor 1 (XAF1) in cancer cell lines. Genomics 70, 113–122 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Yang, Y., Fang, S., Jensen, J. P., Weissman, A. M. & Ashwell, J. D. Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science 288, 874–877 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Hengartner, M. O. Apoptosis. CED-4 is a stranger no more. Nature 388, 714–715 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Ekert, P. G., Silke, J. & Vaux, D. L. Caspase inhibitors. Cell Death Differ. 6, 1081–1086 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Shin, S. et al. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. Biochemistry 40, 1117–1123 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. the Children's Hospital of Eastern Ontario Research Institute, and Ægera Oncology Inc., 401 Smyth Road, Ottawa, K1H 8L1, Ontario, Canada

    Martin Holcik & Robert G. Korneluk

Authors
  1. Martin Holcik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert G. Korneluk
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASE LINKS

XIAP

Bcl-2

cytochrome c

Fas

caspase-9

caspase-3

caspase-7

HIAP1

HIAP2

Apaf-1

Hid

Reaper

Grim

XAF1

cyclin A

cyclin D1

p21Cip1/Waf1

p27Kip1

Akt

FURTHER INFORMATION

Holcik lab

Rights and permissions

Reprints and permissions

About this article

Cite this article

Holcik, M., Korneluk, R. XIAP, the guardian angel. Nat Rev Mol Cell Biol 2, 550–556 (2001). https://doi.org/10.1038/35080103

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35080103

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing