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.

  • Letter
  • Published:

Caenorhabditis elegans CED-9 protein is a bifunctional cell-death inhibitor

Nature volume 390, pages 305–308 (1997)Cite this article

Abstract

The Caenorhabditis elegans gene ced-9 prevents cells from undergoing programmed cell death and encodes a protein similar to the mammalian cell-death inhibitor Bcl-2 (refs 1,2,3,4,5,6,7). We show here that the CED-9 protein is a substrate for the C. elegans cell-death protease CED-3 (refs 8, 9), which is a member of a family of cysteine proteases first defined by CED-3 and human interleukin-1β converting enzyme (ICE)10,11,12. CED-9 can be cleaved by CED-3 at two sites near its amino terminus, and the presence of at least one of these sites is important for complete protection by CED-9 against cell death. Cleavage of CED-9 by CED-3 generates a carboxy-terminal product that resembles Bcl-2 in sequence and in function. Bcl-2 and the baculovirus protein p35, which inhibits cell death in different species through a mechanism that depends on the presence of its cleavage site for the CED-3/ICE family of proteases9,13,14,15,16,17, inhibit cell death additively in C. elegans. Our results indicate that CED-9 prevents programmed cell death in C.elegans through two distinct mechanisms: first, CED-9 may, by analogy with p35 (refs 9, 17), directly inhibit the CED-3 protease by an interaction involving the CED-3 cleavage sites in CED-9; second, CED-9 may directly or indirectly inhibit CED-3 by means of a protective mechanism similar to that used by mammalian Bcl-2.

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: The C. elegans CED-9 protein is a substrate of the CED-3 protease.

Similar content being viewed by others

References

  1. Hengartner, M. O., Ellis, R. E. & Horvitz, H. R. Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature 356, 494–499 (1992).

    Article  ADS  CAS  Google Scholar 

  2. Hengartner, M. O. & Horvitz, H. R. C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76, 665–676 (1994).

    Article  CAS  Google Scholar 

  3. Cleary, M. L., Smith, S. D. & Sklar, J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14; 18) translocation. Cell 47, 19–28 (1986).

    Article  CAS  Google Scholar 

  4. Tsujimoto, Y. & Croce, C. M. Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc. Natl Acad. Sci. USA 83, 5214–5218 (1986).

    Article  ADS  CAS  Google Scholar 

  5. Vaux, D. L., Cory, S. & Adams, J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335, 440–442 (1988).

    Article  ADS  CAS  Google Scholar 

  6. Hockenbery, D., Nunez, G., Milliman, C., Schreiber, R. D. & Korsmeyer, S. J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348, 334–336 (1990).

    Article  ADS  CAS  Google Scholar 

  7. Nunez, G. et al. Deregulated Bcl-2 gene expresison selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J. Immunol. 144, 3602–3610 (1990).

    CAS  PubMed  Google Scholar 

  8. Yuan, J., Shaham, S., Ledoux, S., Ellis, H. M. & Horvitz, H. R. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 75, 641–652 (1993).

    Article  CAS  Google Scholar 

  9. Xue, D. & Horvitz, H. R. Inhibition of the Caenorhabditis elegans cell-death protease CED-3 by a CED-3 cleavage site in baculovirus p35 protein. Nature 377, 248–251 (1995).

    Article  ADS  CAS  Google Scholar 

  10. Thornberry, N. A. et al. Anovel heterodimeric cysteine protease is required for interleukin-1β processing in monocytes. Nure 356, 768–774 (1992).

    ADS  CAS  Google Scholar 

  11. Cerretti, D. P. et al. Molecular cloning of the interleukin-1β converting enzyme. Science 256, 97–100 (1992).

    Article  ADS  CAS  Google Scholar 

  12. Alnemri, E. S. et al. Human ICE/CED-3 protease nomenclature. Cell 87, 171 (1996).

    Article  CAS  Google Scholar 

  13. Clem, R. J., Fechheimer, M. & Miller, L. K. Prevention of apoptosis by a baculovirus gene during infection of insect cells. Science 254, 1388–1390 (1991).

    Article  ADS  CAS  Google Scholar 

  14. Rabizadeh, S., LaCount, D. J., Friesen, P. D. & Bredesen, D. E. Expression of the baculovirus p35 gene inhibits mammalian neural cell death. J. Neurochem. 61, 2318–2321 (1993).

    Article  CAS  Google Scholar 

  15. Sugimoto, A., Friesen, P. D. & Rothman, J. H. Baculovirus p35 prevents developmentally programmed cell death and rescues a ced-9 mutant in the nematode Caenorhabditis elegans. EMBO J. 13, 2023–2028 (1994).

    Article  CAS  Google Scholar 

  16. Hay, B. A., Wolff, T. & Rubin, G. M. Expression of baculovirus P35 prevents cell death in Drosophila. Development 120, 2121–2129 (1994).

    CAS  PubMed  Google Scholar 

  17. Bump, N. J. et al. Inhibition of ICE family proteases by baculovirus anti-aptptotic protein p35. Science 269, 1885–1888 (1995).

    Article  ADS  CAS  Google Scholar 

  18. Xue, D., Shaham, S. & Horvitz, H. R. The Caenorhabditis elegans cell-death protein CED-3 is a cysteine protease with substrate specificities similar to those of the human CPP32 protease. Genes Dev. 10, 1073–1083 (1996).

    Article  CAS  Google Scholar 

  19. Nicholson, D. W. ICE/CED-3-like proteases as therapeutic targets for the control of inappropriate apoptosis. Nature Biotechnol. 14, 297–301 (1996).

    Article  CAS  Google Scholar 

  20. Vaux, D. L., Weissman, I. L. & Kim, S. K. Prevention of programmed cell death in Caenorhabditis elegans by human bcl-2. Science 258, 1955–1957 (1992).

    Article  ADS  CAS  Google Scholar 

  21. Yin, X. M., Oltvai, Z. N. & Korsmeyer, S. J. BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369, 321–323 (1994).

    Article  ADS  CAS  Google Scholar 

  22. Hengartner, M. O. & Horvitz, H. R. Activation of C. elegans cell death protein CED-9 by an amino-acid substitution in a domain conserved in Bcl-2. Nature 369, 318–320 (1994).

    Article  ADS  CAS  Google Scholar 

  23. Shaham, S. & Horvitz, H. R. Developing Caenorhabditis elegans neurons may contain both cell-death protective and killer activities. Genes Dev. 10, 578–591 (1996).

    Article  CAS  Google Scholar 

  24. Ellis, H. M. & Horvitz, H. R. Genetic control of programmed cell death in the nematode C. elegans. Cell 44, 817–829 (1986).

    Article  CAS  Google Scholar 

  25. Yuan, J. & Horvitz, H. R. The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death. Development 116, 309–320 (1992).

    CAS  Google Scholar 

  26. Chinnaiyan, A. M., O'Rourke, K., Lane, B. R. & Dixit, V. M. Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death. Science 275, 1122–1126 (1997).

    Article  CAS  Google Scholar 

  27. Spector, M. S., Desnoyers, S., Hoeppner, D. J. & Hengartner, M. O. Interaction between the C. elegans cell-death regulators CED-9 and CED-4. Nature 385, 653–656 (1997).

    Article  ADS  CAS  Google Scholar 

  28. Wu, D., Wallen, H. D. & Nunez, G. Interaction and regulation of subcellular localization of CED-4 by CED-9. Science 275, 1126–1129 (1997).

    Article  CAS  Google Scholar 

  29. Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning: A Laboratory Manual 2nd edn(Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, (1989)).

    Google Scholar 

  30. Reed, J. C. Double identity for proteins of the Bcl-2 family. Nature 387, 773–776 (1997).

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank members of H.R.H.'s laboratory for comments about the manuscript and the MIT Biopolymers Laboratory for microsequencing analysis. D.X. was supported by postdoctoral fellowships from the Anna Fuller Fund and the Helen Hay Whitney Foundation and is a recipient of a Burroughs Wellcome Fund Career Award in the Biomedical Sciences. H.R.H. is an Investigator of the Howard Hughes Medical Institute.

Author information

Author notes

  1. Ding Xue

    Present address: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado, 80309, USA

Authors and Affiliations

  1. Department of Biology, Howard Hughes Medical Institute, 68-425, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    H. Robert Horvitz

Authors
  1. Ding Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. Robert Horvitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. Robert Horvitz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xue, D., Horvitz, H. Caenorhabditis elegans CED-9 protein is a bifunctional cell-death inhibitor. Nature 390, 305–308 (1997). https://doi.org/10.1038/36889

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/36889

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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