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10.3390/cells10112856
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Article

Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation

by
James Moore
1,*,
Ivan Osinnii
1,
Amandine Grimm
2,
Björn Oettinghaus
3,
Anne Eckert
2,
Stephan Frank
3 and
Erik C. Böttger
1,*
1
Institut für Medizinische Mikrobiologie, Universität Zürich, 8006 Zürich, Switzerland
2
Transfaculty Research Platform Molecular and Cognitive Neuroscience, Universität Basel, 4055 Basel, Switzerland
3
Institut für Pathologie, Universitätsspital Basel, 4031 Basel, Switzerland
*
Authors to whom correspondence should be addressed.
Cells 2021, 10(11), 2856; https://doi.org/10.3390/cells10112856
Submission received: 9 September 2021 / Revised: 14 October 2021 / Accepted: 20 October 2021 / Published: 23 October 2021
(This article belongs to the Special Issue Unfolded Protein Response in Inflammation and Cancer)
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Abstract

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.
Keywords: error-prone translation; ribosomal misreading; mistranslation; proteostasis; liver; ER-UPR; ER stress; Sirtuin-1; RNA-Seq error-prone translation; ribosomal misreading; mistranslation; proteostasis; liver; ER-UPR; ER stress; Sirtuin-1; RNA-Seq

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MDPI and ACS Style

Moore, J.; Osinnii, I.; Grimm, A.; Oettinghaus, B.; Eckert, A.; Frank, S.; Böttger, E.C. Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation. Cells 2021, 10, 2856. https://doi.org/10.3390/cells10112856

AMA Style

Moore J, Osinnii I, Grimm A, Oettinghaus B, Eckert A, Frank S, Böttger EC. Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation. Cells. 2021; 10(11):2856. https://doi.org/10.3390/cells10112856

Chicago/Turabian Style

Moore, James, Ivan Osinnii, Amandine Grimm, Björn Oettinghaus, Anne Eckert, Stephan Frank, and Erik C. Böttger. 2021. "Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation" Cells 10, no. 11: 2856. https://doi.org/10.3390/cells10112856

APA Style

Moore, J., Osinnii, I., Grimm, A., Oettinghaus, B., Eckert, A., Frank, S., & Böttger, E. C. (2021). Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation. Cells, 10(11), 2856. https://doi.org/10.3390/cells10112856

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