Programmed cell death (apoptosis) is essential for the development and homeostasis of metazoans. The central step in the execution of programmed cell death is the activation of caspases. In C. elegans, the core cell death regulators EGL-1(a BH3 domain-containing protein), CED-9 (Bcl-2), and CED-4 (Apaf-1) act in an inhibitory cascade to activate the CED-3 caspase. Here we have identified an additional component
eif-3.K (eukaryotic translation initiation factor 3 subunit k) that acts upstream of
ced-3 to promote programmed cell death. The loss of
eif-3.K reduced cell deaths in both somatic and germ cells, whereas the overexpression of
eif-3.K resulted in a slight but significant increase in cell death. Using a cell-specific promoter, we show that
eif-3.K promotes cell death in a cell-autonomous manner. In addition, the loss of
eif-3.K significantly suppressed cell death-induced through the overexpression of
ced-4, but not
ced-3, indicating a distinct requirement for
eif-3.K in apoptosis. Reciprocally, a loss of
ced-3 suppressed cell death induced by the overexpression of
eif-3.K. These results indicate that
eif-3.K requires
ced-3 to promote programmed cell death and that
eif-3.K acts upstream of
ced-3 to promote this process. The EIF-3.K protein is ubiquitously expressed in embryos and larvae and localizes to the cytoplasm. A structure-function analysis revealed that the 61 amino acid long WH domain of EIF-3.K, potentially involved in protein-DNA/RNA interactions, is both necessary and sufficient for the cell death-promoting activity of EIF-3.K. Because human eIF3k was able to partially substitute for C. elegans
eif-3.K in the promotion of cell death, this WH domain-dependent EIF-3.K-mediated cell death process has potentially been conserved throughout evolution.