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Suppression of CED-3-independent apoptosis by mitochondrial βNAC in Caenorhabditis elegans

Abstract

To ensure cell survival, it is essential that the ubiquitous pro-apoptotic machinery is kept quiescent. As death is irreversible, cells must continually integrate developmental information with regulatory inputs to control the switch between repressing and activating apoptosis. Inappropriate activation or suppression of apoptosis can lead to degenerative pathologies1 or tumorigenesis2, respectively. Here we report that Caenorhabditis elegans inhibitor of cell death-1 (ICD-1) is necessary and sufficient to prevent apoptosis. Loss of ICD-1 leads to inappropriate apoptosis in developing and differentiated cells in various tissues. Although this apoptosis requires CED-4, it occurs independently of CED-3—the caspase essential for developmental apoptosis3—showing that these core pro-apoptotic proteins have separable roles. Overexpressing ICD-1 inhibits the apoptosis of cells that are normally programmed to die. ICD-1 is the β-subunit of the nascent polypeptide-associated complex (βNAC) and contains a putative caspase-cleavage site and caspase recruitment domain. It localizes primarily to mitochondria, underscoring the role of mitochondria in coordinating apoptosis4. Human βNAC is a caspase substrate that is rapidly eliminated in dying cells5,6, suggesting that ICD-1 apoptosis-suppressing activity may be inactivated by caspases.

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Figure 1: Reduction of ICD-1 activity results in increased apoptosis.
Figure 2: Loss of neurons in icd-1(RNAi) animals.
Figure 3: Reduction of ICD-1 activity leads to apoptotic death of intestinal cells.
Figure 4: Overexpression of ICD-1 suppresses developmentally programmed apoptosis.
Figure 5: icd-1(RNAi)-triggered apoptosis is dependent on CED-4 but not CED-3.
Figure 6: ICD-1 is the homologue of human βNAC and colocalizes with mitochondria.

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References

  1. Yuan, J. & Yankner, B. A. Apoptosis in the nervous system. Nature 407, 802–809 (2000)

    Article  CAS  ADS  Google Scholar 

  2. Williams, G. T. Programmed cell death: apoptosis and oncogenesis. Cell 65, 1097–1098 (1991)

    Article  CAS  Google Scholar 

  3. Liu, Q. A. & Hengartner, M. O. The molecular mechanism of programmed cell death in C. elegans. Ann. NY Acad. Sci. 887, 92–104 (1999)

    Article  CAS  ADS  Google Scholar 

  4. Ravagnan, L., Roumier, T. & Kroemer, G. Mitochondria, the killer organelles and their weapons. J. Cell Physiol. 192, 131–137 (2002)

    Article  CAS  Google Scholar 

  5. Brockstedt, E., Otto, A., Rickers, A., Bommert, K. & Wittmann-Liebold, B. Preparative high-resolution two-dimensional electrophoresis enables the identification of RNA polymerase B transcription factor 3 as an apoptosis-associated protein in the human BL60-2 Burkitt lymphoma cell line. J. Protein Chem. 18, 225–231 (1999)

    Article  CAS  Google Scholar 

  6. Thiede, B., Dimmler, C., Siejak, F. & Rudel, T. Predominant identification of RNA-binding proteins in Fas-induced apoptosis by proteome analysis. J. Biol. Chem. 276, 26044–26050 (2001)

    Article  CAS  Google Scholar 

  7. 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 

  8. Ledwich, D., Wu, Y. C., Driscoll, M. & Xue, D. Analysis of programmed cell death in the nematode Caenorhabditis elegans. Methods Enzymol. 322, 76–88 (2000)

    Article  CAS  Google Scholar 

  9. Xu, K., Tavernarakis, N. & Driscoll, M. Necrotic cell death in C. elegans requires the function of calreticulin and regulators of Ca2+ release from the endoplasmic reticulum. Neuron 31, 957–971 (2001)

    Article  CAS  Google Scholar 

  10. Hersh, B. M., Hartwieg, E. & Horvitz, H. R. The Caenorhabditis elegans mucolipin-like gene cup-5 is essential for viability and regulates lysosomes in multiple cell types. Proc. Natl Acad. Sci. USA 99, 4355–4360 (2002)

    Article  CAS  ADS  Google Scholar 

  11. Sulston, J. E., Albertson, D. G. & Thomson, J. N. The Caenorhabditis elegans male: postembryonic development of nongonadal structures. Dev. Biol. 78, 542–576 (1980)

    Article  CAS  Google Scholar 

  12. 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  CAS  ADS  Google Scholar 

  13. Sulston, J. E., Schierenberg, E., White, J. G. & Thomson, J. N. The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev. Biol. 100, 64–119 (1983)

    Article  CAS  Google Scholar 

  14. 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 

  15. Rospert, S., Dubaquie, Y. & Gautschi, M. Nascent-polypeptide-associated complex. Cell Mol. Life Sci. 59, 1632–1639 (2002)

    Article  CAS  Google Scholar 

  16. Takahashi, M., Mukai, H., Toshimori, M., Miyamoto, M. & Ono, Y. Proteolytic activation of PKN by caspase-3 or related protease during apoptosis. Proc. Natl Acad. Sci. USA 95, 11566–11571 (1998)

    Article  CAS  ADS  Google Scholar 

  17. Vaughn, D. E., Rodriguez, J., Lazebnik, Y. & Joshua-Tor, L. Crystal structure of Apaf-1 caspase recruitment domain: an α-helical Greek key fold for apoptotic signaling. J. Mol. Biol. 293, 439–447 (1999)

    Article  CAS  Google Scholar 

  18. Seshagiri, S., Chang, W. T. & Miller, L. K. Mutational analysis of Caenorhabditis elegans CED-4. FEBS Lett. 428, 71–74 (1998)

    Article  CAS  Google Scholar 

  19. Shaham, S. Identification of multiple Caenorhabditis elegans caspases and their potential roles in proteolytic cascades. J. Biol. Chem. 273, 35109–35117 (1998)

    Article  CAS  Google Scholar 

  20. Hodgkin, J. in C. elegans. (eds Riddle, D. L., Blumenthal, T., Meyer, B. J. & Priess, J. R.) 881–1047 (Cold Spring Harbor Laboratory Press, Plainview, NY, 1997)

    Google Scholar 

  21. Lewis, J. A. & Fleming, J. T. in Caenorhabditis elegans: Modern Biological Analyses of an Organism (eds Epstein, H. F. & Shakes, D. C.) 4–27 (Academic, San Diego, 1995)

    Google Scholar 

  22. Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989)

    Google Scholar 

  23. Kamath, R. S., Martinez-Campos, M., Zipperlen, P., Fraser, A. G. & Ahringer, J. Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol. 2, Research0002 〈http://genomebiology.com/2000/2/1/research/0002〉 (2001)

  24. Maeda, I., Kohara, Y., Yamamoto, M. & Sugimoto, A. Large-scale analysis of gene function in Caenorhabditis elegans by high-throughput RNAi. Curr. Biol. 11, 171–176 (2001)

    Article  CAS  Google Scholar 

  25. Parrish, S., Fleenor, J., Xu, S., Mello, C. & Fire, A. Functional anatomy of a dsRNA trigger: differential requirement for the two trigger strands in RNA interference. Mol. Cell 6, 1077–1087 (2000)

    Article  CAS  Google Scholar 

  26. Hall, D. in Caenorhabditis elegans: Modern Biological Analysis of an Organism (eds Epstein, H. F. & Shakes, D. C.) 396–436 (Academic, San Diego, 1995)

    Google Scholar 

  27. Miller, D. M. & Shakes, D. C. in Caenorhabditis elegans: Modern Biological Analysis of an Organism (eds Epstein, H. F. & Shakes, D. C.) 365–395 (Academic, San Diego, 1995)

    Book  Google Scholar 

  28. Fukushige, T., Hawkins, M. G. & McGhee, J. D. The GATA-factor elt-2 is essential for formation of the Caenorhabditis elegans intestine. Dev. Biol. 198, 286–302 (1998)

    CAS  PubMed  Google Scholar 

  29. Loo, D. T. & Rillema, J. R. Measurement of cell death. Methods Cell Biol. 57, 251–264 (1998)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank D. Pilgrim for the edIs20 strain; J. White, K. Strohmaier, K. Linberg and G. Lewis for advice on electron microscopy; B. Derry and T. McCloskey for comments on the manuscript; and members of the Rothman laboratory for discussions. Some nematode strains were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources. This work was supported by a Cancer Center of Santa Barbara postdoctoral fellowship to T.B. and by grants from the NIH and the March of Dimes Birth Defects Foundation to J.H.R.

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Correspondence to Joel H. Rothman.

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The University of California has filed a patent application based, in part, on the described findings.

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Bloss, T., Witze, E. & Rothman, J. Suppression of CED-3-independent apoptosis by mitochondrial βNAC in Caenorhabditis elegans. Nature 424, 1066–1071 (2003). https://doi.org/10.1038/nature01920

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