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:	James Moore, Ivan Osinnii, Amandine Grimm, Björn Oettinghaus, Anne Eckert, Stephan Frank, Erik C. Böttger
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	error-prone translation ribosomal misreading mistranslation proteostasis liver ER-UPR Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1d4f3cec56d341cc86354d93001d0c3c
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spelling	oai:doaj.org-article:1d4f3cec56d341cc86354d93001d0c3c2021-11-25T17:08:06ZSilencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation10.3390/cells101128562073-4409https://doaj.org/article/1d4f3cec56d341cc86354d93001d0c3c2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2856https://doaj.org/toc/2073-4409Translational 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 <i>Rps2</i>-A226Y ribosomal ambiguity (<i>ram</i>) mutation to increase the translation error rate across all proteins. We found that <i>Rps2</i>-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.James MooreIvan OsinniiAmandine GrimmBjörn OettinghausAnne EckertStephan FrankErik C. BöttgerMDPI AGarticleerror-prone translationribosomal misreadingmistranslationproteostasisliverER-UPRBiology (General)QH301-705.5ENCells, Vol 10, Iss 2856, p 2856 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	error-prone translation ribosomal misreading mistranslation proteostasis liver ER-UPR Biology (General) QH301-705.5
spellingShingle	error-prone translation ribosomal misreading mistranslation proteostasis liver ER-UPR Biology (General) QH301-705.5 James Moore Ivan Osinnii Amandine Grimm Björn Oettinghaus Anne Eckert Stephan Frank Erik C. Böttger Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation
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 <i>Rps2</i>-A226Y ribosomal ambiguity (<i>ram</i>) mutation to increase the translation error rate across all proteins. We found that <i>Rps2</i>-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	article
author	James Moore Ivan Osinnii Amandine Grimm Björn Oettinghaus Anne Eckert Stephan Frank Erik C. Böttger
author_facet	James Moore Ivan Osinnii Amandine Grimm Björn Oettinghaus Anne Eckert Stephan Frank Erik C. Böttger
author_sort	James Moore
title	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_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_sort	silencing of the er and integrative stress responses in the liver of mice with error-prone translation
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1d4f3cec56d341cc86354d93001d0c3c
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Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation

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