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EIF2B2 mutations in vanishing white matter disease hypersuppress translation and delay recovery during the integrated stress response

Mutations in eIF2B genes cause vanishing white matter disease (VWMD), a fatal leukodystrophy that can manifest following physical trauma or illness, conditions that activate the integrated stress response (ISR). EIF2B is the guanine exchange factor for eIF2, facilitating ternary complex formation an...

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Autores principales: Moon, Stephanie L., Parker, Roy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959252/
https://www.ncbi.nlm.nih.gov/pubmed/29632131
http://dx.doi.org/10.1261/rna.066563.118
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author Moon, Stephanie L.
Parker, Roy
author_facet Moon, Stephanie L.
Parker, Roy
author_sort Moon, Stephanie L.
collection PubMed
description Mutations in eIF2B genes cause vanishing white matter disease (VWMD), a fatal leukodystrophy that can manifest following physical trauma or illness, conditions that activate the integrated stress response (ISR). EIF2B is the guanine exchange factor for eIF2, facilitating ternary complex formation and translation initiation. During the ISR, eIF2α is phosphorylated and inhibits eIF2B, causing global translation suppression and stress-induced gene translation, allowing stress adaptation and recovery. We demonstrate that VWMD patient cells hypersuppress translation during the ISR caused by acute ER stress, delaying stress-induced gene expression and interrupting a negative feedback loop that allows translational recovery by GADD34-mediated dephosphorylation of phospho-eIF2α. Thus, cells from VWMD patients undergo a prolonged state of translational hyperrepression and fail to recover from stress. We demonstrate that small molecules targeting eIF2B or the eIF2α kinase PERK rescue translation defects in patient cells. Therefore, defects in the ISR could contribute to white matter loss in VWMD.
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spelling pubmed-59592522018-06-01 EIF2B2 mutations in vanishing white matter disease hypersuppress translation and delay recovery during the integrated stress response Moon, Stephanie L. Parker, Roy RNA Article Mutations in eIF2B genes cause vanishing white matter disease (VWMD), a fatal leukodystrophy that can manifest following physical trauma or illness, conditions that activate the integrated stress response (ISR). EIF2B is the guanine exchange factor for eIF2, facilitating ternary complex formation and translation initiation. During the ISR, eIF2α is phosphorylated and inhibits eIF2B, causing global translation suppression and stress-induced gene translation, allowing stress adaptation and recovery. We demonstrate that VWMD patient cells hypersuppress translation during the ISR caused by acute ER stress, delaying stress-induced gene expression and interrupting a negative feedback loop that allows translational recovery by GADD34-mediated dephosphorylation of phospho-eIF2α. Thus, cells from VWMD patients undergo a prolonged state of translational hyperrepression and fail to recover from stress. We demonstrate that small molecules targeting eIF2B or the eIF2α kinase PERK rescue translation defects in patient cells. Therefore, defects in the ISR could contribute to white matter loss in VWMD. Cold Spring Harbor Laboratory Press 2018-06 /pmc/articles/PMC5959252/ /pubmed/29632131 http://dx.doi.org/10.1261/rna.066563.118 Text en © 2018 Moon and Parker; Published by Cold Spring Harbor Laboratory Press for the RNA Society http://creativecommons.org/licenses/by/4.0/ This article, published in RNA, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Moon, Stephanie L.
Parker, Roy
EIF2B2 mutations in vanishing white matter disease hypersuppress translation and delay recovery during the integrated stress response
title EIF2B2 mutations in vanishing white matter disease hypersuppress translation and delay recovery during the integrated stress response
title_full EIF2B2 mutations in vanishing white matter disease hypersuppress translation and delay recovery during the integrated stress response
title_fullStr EIF2B2 mutations in vanishing white matter disease hypersuppress translation and delay recovery during the integrated stress response
title_full_unstemmed EIF2B2 mutations in vanishing white matter disease hypersuppress translation and delay recovery during the integrated stress response
title_short EIF2B2 mutations in vanishing white matter disease hypersuppress translation and delay recovery during the integrated stress response
title_sort eif2b2 mutations in vanishing white matter disease hypersuppress translation and delay recovery during the integrated stress response
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959252/
https://www.ncbi.nlm.nih.gov/pubmed/29632131
http://dx.doi.org/10.1261/rna.066563.118
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