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 cells^5,6, suggesting that ICD-1 apoptosis-suppressing activity may be inactivated by caspases.