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Targeting EDEM protects against ER stress and improves development and survival in C. elegans

EDEM-1, EDEM-2 and EDEM-3 are key players for the quality control of newly synthesized proteins in the endoplasmic reticulum (ER) by accelerating disposal and degradation of misfolded proteins through ER Associated Degradation (ERAD). Although many previous studies reported the role of individual ER...

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Autores principales: Ghenea, Simona, Chiritoiu, Marioara, Tacutu, Robi, Miranda-Vizuete, Antonio, Petrescu, Stefana Maria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912907/
https://www.ncbi.nlm.nih.gov/pubmed/35192599
http://dx.doi.org/10.1371/journal.pgen.1010069
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author Ghenea, Simona
Chiritoiu, Marioara
Tacutu, Robi
Miranda-Vizuete, Antonio
Petrescu, Stefana Maria
author_facet Ghenea, Simona
Chiritoiu, Marioara
Tacutu, Robi
Miranda-Vizuete, Antonio
Petrescu, Stefana Maria
author_sort Ghenea, Simona
collection PubMed
description EDEM-1, EDEM-2 and EDEM-3 are key players for the quality control of newly synthesized proteins in the endoplasmic reticulum (ER) by accelerating disposal and degradation of misfolded proteins through ER Associated Degradation (ERAD). Although many previous studies reported the role of individual ERAD components especially in cell-based systems, still little is known about the consequences of ERAD dysfunction under physiological and ER stress conditions in the context of a multicellular organism. Here we report the first individual and combined characterization and functional interplay of EDEM proteins in Caenorhabditis elegans using single, double, and triple mutant combinations. We found that EDEM-2 has a major role in the clearance of misfolded proteins from ER under physiological conditions, whereas EDEM-1 and EDEM-3 roles become prominent under acute ER stress. In contrast to SEL-1 loss, the loss of EDEMs in an intact organism induces only a modest ER stress under physiological conditions. In addition, chronic impairment of EDEM functioning attenuated both XBP-1 activation and up-regulation of the stress chaperone GRP78/BiP, in response to acute ER stress. We also show that pre-conditioning to EDEM loss in acute ER stress restores ER homeostasis and promotes survival by activating ER hormesis. We propose a novel role for EDEM in fine-tuning the ER stress responsiveness that affects ER homeostasis and survival.
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spelling pubmed-89129072022-03-11 Targeting EDEM protects against ER stress and improves development and survival in C. elegans Ghenea, Simona Chiritoiu, Marioara Tacutu, Robi Miranda-Vizuete, Antonio Petrescu, Stefana Maria PLoS Genet Research Article EDEM-1, EDEM-2 and EDEM-3 are key players for the quality control of newly synthesized proteins in the endoplasmic reticulum (ER) by accelerating disposal and degradation of misfolded proteins through ER Associated Degradation (ERAD). Although many previous studies reported the role of individual ERAD components especially in cell-based systems, still little is known about the consequences of ERAD dysfunction under physiological and ER stress conditions in the context of a multicellular organism. Here we report the first individual and combined characterization and functional interplay of EDEM proteins in Caenorhabditis elegans using single, double, and triple mutant combinations. We found that EDEM-2 has a major role in the clearance of misfolded proteins from ER under physiological conditions, whereas EDEM-1 and EDEM-3 roles become prominent under acute ER stress. In contrast to SEL-1 loss, the loss of EDEMs in an intact organism induces only a modest ER stress under physiological conditions. In addition, chronic impairment of EDEM functioning attenuated both XBP-1 activation and up-regulation of the stress chaperone GRP78/BiP, in response to acute ER stress. We also show that pre-conditioning to EDEM loss in acute ER stress restores ER homeostasis and promotes survival by activating ER hormesis. We propose a novel role for EDEM in fine-tuning the ER stress responsiveness that affects ER homeostasis and survival. Public Library of Science 2022-02-22 /pmc/articles/PMC8912907/ /pubmed/35192599 http://dx.doi.org/10.1371/journal.pgen.1010069 Text en © 2022 Ghenea et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Ghenea, Simona
Chiritoiu, Marioara
Tacutu, Robi
Miranda-Vizuete, Antonio
Petrescu, Stefana Maria
Targeting EDEM protects against ER stress and improves development and survival in C. elegans
title Targeting EDEM protects against ER stress and improves development and survival in C. elegans
title_full Targeting EDEM protects against ER stress and improves development and survival in C. elegans
title_fullStr Targeting EDEM protects against ER stress and improves development and survival in C. elegans
title_full_unstemmed Targeting EDEM protects against ER stress and improves development and survival in C. elegans
title_short Targeting EDEM protects against ER stress and improves development and survival in C. elegans
title_sort targeting edem protects against er stress and improves development and survival in c. elegans
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912907/
https://www.ncbi.nlm.nih.gov/pubmed/35192599
http://dx.doi.org/10.1371/journal.pgen.1010069
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