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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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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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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DOI: https://doi.org/10.1038/nature01920
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