Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation
| Autor: | Erik C. Böttger, Stephan Frank, Anne Eckert, Ivan Osinnii, Amandine Grimm, Björn Oettinghaus, James M. Moore |
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| Přispěvatelé: | University of Zurich, Moore, James, Böttger, Erik C |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Proteasome Endopeptidase Complex
Sirtuin-1 QH301-705.5 Down-Regulation Mice Transgenic 610 Medicine & health 2700 General Medicine liver Article Stress granule Sirtuin 1 Downregulation and upregulation mistranslation Animals Integrated stress response Chronic stress Gene Silencing RNA-Seq Biology (General) proteostasis ATF6 Chemistry 10179 Institute of Medical Microbiology Translation (biology) General Medicine Endoplasmic Reticulum Stress Stress Granules ER-UPR Mitochondria Up-Regulation Cell biology error-prone translation Disease Models Animal Proteostasis Protein Biosynthesis Unfolded Protein Response Unfolded protein response 570 Life sciences biology ER stress ribosomal misreading |
| Zdroj: | Cells, Vol 10, Iss 2856, p 2856 (2021) Cells Volume 10 Issue 11 |
| ISSN: | 2073-4409 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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