The Translational Regulators GCN-1 and ABCF-3 Act Together to Promote Apoptosis in C. elegans
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 unexplor...
| Main Authors: | , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
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Public Library of Science
2014
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| Online Access: | http://hdl.handle.net/1721.1/90973 https://orcid.org/0000-0002-9964-9613 |
| _version_ | 1826192282069499904 |
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| author | Hirose, Takashi Horvitz, Howard Robert |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Hirose, Takashi Horvitz, Howard Robert |
| author_sort | Hirose, Takashi |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T09:08:47Z |
| format | Article |
| id | mit-1721.1/90973 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:08:47Z |
| publishDate | 2014 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/909732022-09-26T10:45:32Z The Translational Regulators GCN-1 and ABCF-3 Act Together to Promote Apoptosis in C. elegans Hirose, Takashi Horvitz, Howard Robert Massachusetts Institute of Technology. Department of Biology Hirose, Takashi Horvitz, H. Robert 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. Howard Hughes Medical Institute 2014-10-20T12:16:15Z 2014-10-20T12:16:15Z 2014-08 2013-10 Article http://purl.org/eprint/type/JournalArticle 1553-7404 1553-7390 http://hdl.handle.net/1721.1/90973 Hirose, Takashi, and H. Robert Horvitz. “The Translational Regulators GCN-1 and ABCF-3 Act Together to Promote Apoptosis in C. Elegans.” Edited by Andrew D. Chisholm. PLoS Genet 10, no. 8 (August 7, 2014): e1004512. https://orcid.org/0000-0002-9964-9613 en_US http://dx.doi.org/10.1371/journal.pgen.1004512 PLoS Genetics Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science Public Library of Science |
| spellingShingle | Hirose, Takashi Horvitz, Howard Robert The Translational Regulators GCN-1 and ABCF-3 Act Together to Promote Apoptosis in C. elegans |
| title | The Translational Regulators GCN-1 and ABCF-3 Act Together to Promote Apoptosis in C. elegans |
| title_full | The Translational Regulators GCN-1 and ABCF-3 Act Together to Promote Apoptosis in C. elegans |
| title_fullStr | The Translational Regulators GCN-1 and ABCF-3 Act Together to Promote Apoptosis in C. elegans |
| title_full_unstemmed | The Translational Regulators GCN-1 and ABCF-3 Act Together to Promote Apoptosis in C. elegans |
| title_short | The Translational Regulators GCN-1 and ABCF-3 Act Together to Promote Apoptosis in C. elegans |
| title_sort | translational regulators gcn 1 and abcf 3 act together to promote apoptosis in c elegans |
| url | http://hdl.handle.net/1721.1/90973 https://orcid.org/0000-0002-9964-9613 |
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