Back to Search Start Over

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

Authors :
James Moore
Ivan Osinnii
Amandine Grimm
Björn Oettinghaus
Anne Eckert
Stephan Frank
Erik C. Böttger
Source :
Cells, Vol 10, Iss 11, p 2856 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

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.

Details

Language :
English
ISSN :
20734409
Volume :
10
Issue :
11
Database :
Directory of Open Access Journals
Journal :
Cells
Publication Type :
Academic Journal
Accession number :
edsdoj.1d4f3cec56d341cc86354d93001d0c3c
Document Type :
article
Full Text :
https://doi.org/10.3390/cells10112856