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Cellular eIF2B subunit localization: implications for the integrated stress response and its control by small molecule drugs
Eukaryotic initiation factor 2 (eIF2) is a G protein critical for translation. It is tightly regulated in the integrated stress response (ISR) via phosphorylation of eIF2α and the subsequent control of eukaryotic initiation factor 2B (eIF2B), a multisubunit guanine nucleotide exchange factor. Throug...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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The American Society for Cell Biology
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589909/ https://www.ncbi.nlm.nih.gov/pubmed/30726166 http://dx.doi.org/10.1091/mbc.E18-08-0538 |
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author | Hodgson, Rachel E. Varanda, Beatriz A. Ashe, Mark P. Allen, K. Elizabeth Campbell, Susan G. |
author_facet | Hodgson, Rachel E. Varanda, Beatriz A. Ashe, Mark P. Allen, K. Elizabeth Campbell, Susan G. |
author_sort | Hodgson, Rachel E. |
collection | PubMed |
description | Eukaryotic initiation factor 2 (eIF2) is a G protein critical for translation. It is tightly regulated in the integrated stress response (ISR) via phosphorylation of eIF2α and the subsequent control of eukaryotic initiation factor 2B (eIF2B), a multisubunit guanine nucleotide exchange factor. Through studying the localization of eIF2B subunits, we identified cytoplasmic eIF2B bodies in mammalian cells. We highlight a relationship between body size and the eIF2B subunits localizing to them; larger bodies contain all subunits and smaller bodies contain predominantly catalytic subunits. eIF2 localizes to eIF2B bodies and shuttles within these bodies in a manner that correlates with eIF2B activity. On stress, eIF2α-P localizes predominately to larger bodies and results in a decreased shuttling of eIF2. Interestingly, drugs that inhibit the ISR can rescue eIF2 shuttling in a manner correlating to levels of eIF2α-P. In contrast, smaller bodies show increased eIF2 shuttling in response to stress, which is accompanied by the localization of eIF2Bδ to these bodies, suggesting the formation of a novel trimeric complex of eIF2B. This response is mimicked by ISR-inhibiting drugs, providing insight into their potential mechanism of action. This study provides evidence that the composition and function of mammalian eIF2B bodies are regulated by the ISR and the drugs that control it. |
format | Online Article Text |
id | pubmed-6589909 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-65899092019-07-09 Cellular eIF2B subunit localization: implications for the integrated stress response and its control by small molecule drugs Hodgson, Rachel E. Varanda, Beatriz A. Ashe, Mark P. Allen, K. Elizabeth Campbell, Susan G. Mol Biol Cell Articles Eukaryotic initiation factor 2 (eIF2) is a G protein critical for translation. It is tightly regulated in the integrated stress response (ISR) via phosphorylation of eIF2α and the subsequent control of eukaryotic initiation factor 2B (eIF2B), a multisubunit guanine nucleotide exchange factor. Through studying the localization of eIF2B subunits, we identified cytoplasmic eIF2B bodies in mammalian cells. We highlight a relationship between body size and the eIF2B subunits localizing to them; larger bodies contain all subunits and smaller bodies contain predominantly catalytic subunits. eIF2 localizes to eIF2B bodies and shuttles within these bodies in a manner that correlates with eIF2B activity. On stress, eIF2α-P localizes predominately to larger bodies and results in a decreased shuttling of eIF2. Interestingly, drugs that inhibit the ISR can rescue eIF2 shuttling in a manner correlating to levels of eIF2α-P. In contrast, smaller bodies show increased eIF2 shuttling in response to stress, which is accompanied by the localization of eIF2Bδ to these bodies, suggesting the formation of a novel trimeric complex of eIF2B. This response is mimicked by ISR-inhibiting drugs, providing insight into their potential mechanism of action. This study provides evidence that the composition and function of mammalian eIF2B bodies are regulated by the ISR and the drugs that control it. The American Society for Cell Biology 2019-04-01 /pmc/articles/PMC6589909/ /pubmed/30726166 http://dx.doi.org/10.1091/mbc.E18-08-0538 Text en © 2019 Hodgson et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License. |
spellingShingle | Articles Hodgson, Rachel E. Varanda, Beatriz A. Ashe, Mark P. Allen, K. Elizabeth Campbell, Susan G. Cellular eIF2B subunit localization: implications for the integrated stress response and its control by small molecule drugs |
title | Cellular eIF2B subunit localization: implications for the integrated stress response and its control by small molecule drugs |
title_full | Cellular eIF2B subunit localization: implications for the integrated stress response and its control by small molecule drugs |
title_fullStr | Cellular eIF2B subunit localization: implications for the integrated stress response and its control by small molecule drugs |
title_full_unstemmed | Cellular eIF2B subunit localization: implications for the integrated stress response and its control by small molecule drugs |
title_short | Cellular eIF2B subunit localization: implications for the integrated stress response and its control by small molecule drugs |
title_sort | cellular eif2b subunit localization: implications for the integrated stress response and its control by small molecule drugs |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589909/ https://www.ncbi.nlm.nih.gov/pubmed/30726166 http://dx.doi.org/10.1091/mbc.E18-08-0538 |
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