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Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation
Translational errors frequently arise during protein synthesis, producing misfolded and dysfunctional proteins. Chronic stress resulting from translation errors may be particularly relevant in tissues that must synthesize and secrete large amounts of secretory proteins. Here, we studied the proteost...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616113/ https://www.ncbi.nlm.nih.gov/pubmed/34831079 http://dx.doi.org/10.3390/cells10112856 |
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author | Moore, James Osinnii, Ivan Grimm, Amandine Oettinghaus, Björn Eckert, Anne Frank, Stephan Böttger, Erik C. |
author_facet | Moore, James Osinnii, Ivan Grimm, Amandine Oettinghaus, Björn Eckert, Anne Frank, Stephan Böttger, Erik C. |
author_sort | Moore, James |
collection | PubMed |
description | Translational errors frequently arise during protein synthesis, producing misfolded and dysfunctional proteins. Chronic stress resulting from translation errors may be particularly relevant in tissues that must synthesize and secrete large amounts of secretory proteins. Here, we studied the proteostasis networks in the liver of mice that express the Rps2-A226Y ribosomal ambiguity (ram) mutation to increase the translation error rate across all proteins. We found that Rps2-A226Y mice lack activation of the eIF2 kinase/ATF4 pathway, the main component of the integrated stress response (ISR), as well as the IRE1 and ATF6 pathways of the ER unfolded protein response (ER-UPR). Instead, we found downregulation of chronic ER stress responses, as indicated by reduced gene expression for lipogenic pathways and acute phase proteins, possibly via upregulation of Sirtuin-1. In parallel, we observed activation of alternative proteostasis responses, including the proteasome and the formation of stress granules. Together, our results point to a concerted response to error-prone translation to alleviate ER stress in favor of activating alternative proteostasis mechanisms, most likely to avoid cell damage and apoptotic pathways, which would result from persistent activation of the ER and integrated stress responses. |
format | Online Article Text |
id | pubmed-8616113 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-86161132021-11-26 Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation Moore, James Osinnii, Ivan Grimm, Amandine Oettinghaus, Björn Eckert, Anne Frank, Stephan Böttger, Erik C. Cells Article Translational errors frequently arise during protein synthesis, producing misfolded and dysfunctional proteins. Chronic stress resulting from translation errors may be particularly relevant in tissues that must synthesize and secrete large amounts of secretory proteins. Here, we studied the proteostasis networks in the liver of mice that express the Rps2-A226Y ribosomal ambiguity (ram) mutation to increase the translation error rate across all proteins. We found that Rps2-A226Y mice lack activation of the eIF2 kinase/ATF4 pathway, the main component of the integrated stress response (ISR), as well as the IRE1 and ATF6 pathways of the ER unfolded protein response (ER-UPR). Instead, we found downregulation of chronic ER stress responses, as indicated by reduced gene expression for lipogenic pathways and acute phase proteins, possibly via upregulation of Sirtuin-1. In parallel, we observed activation of alternative proteostasis responses, including the proteasome and the formation of stress granules. Together, our results point to a concerted response to error-prone translation to alleviate ER stress in favor of activating alternative proteostasis mechanisms, most likely to avoid cell damage and apoptotic pathways, which would result from persistent activation of the ER and integrated stress responses. MDPI 2021-10-23 /pmc/articles/PMC8616113/ /pubmed/34831079 http://dx.doi.org/10.3390/cells10112856 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Moore, James Osinnii, Ivan Grimm, Amandine Oettinghaus, Björn Eckert, Anne Frank, Stephan Böttger, Erik C. Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation |
title | Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation |
title_full | Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation |
title_fullStr | Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation |
title_full_unstemmed | Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation |
title_short | Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation |
title_sort | silencing of the er and integrative stress responses in the liver of mice with error-prone translation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616113/ https://www.ncbi.nlm.nih.gov/pubmed/34831079 http://dx.doi.org/10.3390/cells10112856 |
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