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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...

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Autores principales: Moore, James, Osinnii, Ivan, Grimm, Amandine, Oettinghaus, Björn, Eckert, Anne, Frank, Stephan, Böttger, Erik C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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