title: C. elegans EIF-3.K promotes programmed cell death through CED-3 caspase.
abstract: 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.
authors.affiliation: Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan.
authors.forename: Chun-Yi
authors.initials: CY
authors.lastname: Huang
authors.forename: Jia-Yun
authors.initials: JY
authors.lastname: Chen
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Wu
authors.forename: Chieh-Hsiang
authors.initials: CH
authors.lastname: Tan
authors.forename: Ruei-Ying
authors.initials: RY
authors.lastname: Tzeng
authors.forename: Pei-Ju
authors.initials: PJ
authors.lastname: Lu
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Wu
authors.forename: Ruey-Hwa
authors.initials: RH
authors.lastname: Chen
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Wu
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis* / Q000235:genetics; D020169:Caspases / Q000096:biosynthesis* / Q000235:genetics; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D039621:Eukaryotic Initiation Factor-3; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005816:Genetic Complementation Test; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007814:Larva / Q000166:cytology / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D039621:Eukaryotic Initiation Factor-3; D020169:Caspases; C089223:ced-3 protein, C elegans