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.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Yuan, J. & Yankner, B. A. Apoptosis in the nervous system. Nature 407, 802–809 (2000)
Williams, G. T. Programmed cell death: apoptosis and oncogenesis. Cell 65, 1097–1098 (1991)
Liu, Q. A. & Hengartner, M. O. The molecular mechanism of programmed cell death in C. elegans. Ann. NY Acad. Sci. 887, 92–104 (1999)
Ravagnan, L., Roumier, T. & Kroemer, G. Mitochondria, the killer organelles and their weapons. J. Cell Physiol. 192, 131–137 (2002)
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)
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)
Ellis, H. M. & Horvitz, H. R. Genetic control of programmed cell death in the nematode C. elegans. Cell 44, 817–829 (1986)
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)
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)
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)
Sulston, J. E., Albertson, D. G. & Thomson, J. N. The Caenorhabditis elegans male: postembryonic development of nongonadal structures. Dev. Biol. 78, 542–576 (1980)
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)
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)
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)
Rospert, S., Dubaquie, Y. & Gautschi, M. Nascent-polypeptide-associated complex. Cell Mol. Life Sci. 59, 1632–1639 (2002)
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)
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)
Seshagiri, S., Chang, W. T. & Miller, L. K. Mutational analysis of Caenorhabditis elegans CED-4. FEBS Lett. 428, 71–74 (1998)
Shaham, S. Identification of multiple Caenorhabditis elegans caspases and their potential roles in proteolytic cascades. J. Biol. Chem. 273, 35109–35117 (1998)
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)
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)
Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989)
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)
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)
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)
Hall, D. in Caenorhabditis elegans: Modern Biological Analysis of an Organism (eds Epstein, H. F. & Shakes, D. C.) 396–436 (Academic, San Diego, 1995)
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)
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)
Loo, D. T. & Rillema, J. R. Measurement of cell death. Methods Cell Biol. 57, 251–264 (1998)
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.
The University of California has filed a patent application based, in part, on the described findings.
About this article
Cite this article
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
Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity
Signal Transduction and Targeted Therapy (2021)
A ribosome-associated chaperone enables substrate triage in a cotranslational protein targeting complex
Nature Communications (2020)
Positive expression of basic transcription factor 3 predicts poor survival of colorectal cancer patients: possible mechanisms involved
Cell Death & Disease (2019)
Phylogenetic and functional analysis of the basic transcription factor gene BTF3 from Jatropha curcas
Plant Growth Regulation (2017)
Cell Death & Differentiation (2016)