title: The translational regulators GCN-1 and ABCF-3 act together to promote apoptosis in C. elegans.
abstract: The proper regulation of apoptosis requires precise spatial and temporal control of gene expression. While the transcriptional and translational activation of pro-apoptotic genes is known to be crucial to triggering apoptosis, how different mechanisms cooperate to drive apoptosis is largely unexplored. Here we report that pro-apoptotic transcriptional and translational regulators act in distinct pathways to promote programmed cell death. We show that the evolutionarily conserved C. elegans translational regulators GCN-1 and ABCF-3 contribute to promoting the deaths of most somatic cells during development. GCN-1 and ABCF-3 are not obviously involved in the physiological germ-cell deaths that occur during oocyte maturation. By striking contrast, these proteins play an essential role in the deaths of germ cells in response to ionizing irradiation. GCN-1 and ABCF-3 are similarly co-expressed in many somatic and germ cells and physically interact in vivo, suggesting that GCN-1 and ABCF-3 function as members of a protein complex. GCN-1 and ABCF-3 are required for the basal level of phosphorylation of eukaryotic initiation factor 2α (eIF2α), an evolutionarily conserved regulator of mRNA translation. The S. cerevisiae homologs of GCN-1 and ABCF-3, which are known to control eIF2α phosphorylation, can substitute for the worm proteins in promoting somatic cell deaths in C. elegans. We conclude that GCN-1 and ABCF-3 likely control translational initiation in C. elegans. GCN-1 and ABCF-3 act independently of the anti-apoptotic BCL-2 homolog CED-9 and of transcriptional regulators that upregulate the pro-apoptotic BH3-only gene egl-1. Our results suggest that GCN-1 and ABCF-3 function in a pathway distinct from the canonical CED-9-regulated cell-death execution pathway. We propose that the translational regulators GCN-1 and ABCF-3 maternally contribute to general apoptosis in C. elegans via a novel pathway and that the function of GCN-1 and ABCF-3 in apoptosis might be evolutionarily conserved.
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hirose
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: H Robert
authors.initials: HR
authors.lastname: Horvitz
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis / Q000235:genetics*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D015852:Eukaryotic Initiation Factor-2 / Q000096:biosynthesis / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000528:radiation effects; D005854:Germ Cells / Q000528:radiation effects; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D011839:Radiation, Ionizing
chemical_list: D018528:ATP-Binding Cassette Transporters; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger; C578468:gcn-1 protein, C elegans
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