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USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway

An imbalance in cellular homeostasis occurring as a result of protein misfolding and aggregation contributes to the pathogeneses of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we report the identification of a ubiquitin-specific protease, USP7, as a regulatory sw...

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Autores principales: Zhang, Tao, Periz, Goran, Lu, Yu-Ning, Wang, Jiou
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668097/
https://www.ncbi.nlm.nih.gov/pubmed/33106424
http://dx.doi.org/10.1073/pnas.2014349117
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author Zhang, Tao
Periz, Goran
Lu, Yu-Ning
Wang, Jiou
author_facet Zhang, Tao
Periz, Goran
Lu, Yu-Ning
Wang, Jiou
author_sort Zhang, Tao
collection PubMed
description An imbalance in cellular homeostasis occurring as a result of protein misfolding and aggregation contributes to the pathogeneses of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we report the identification of a ubiquitin-specific protease, USP7, as a regulatory switch in a protein quality-control system that defends against proteotoxicity. A genome-wide screen in a Caenorhabditis elegans model of SOD1-linked ALS identified the USP7 ortholog as a suppressor of proteotoxicity in the nervous system. The actions of USP7 orthologs on misfolded proteins were found to be conserved in Drosophila and mammalian cells. USP7 acts on protein quality control through the SMAD2 transcription modulator of the transforming growth factor β pathway, which activates autophagy and enhances the clearance of misfolded proteins. USP7 deubiquitinates the E3 ubiquitin ligase NEDD4L, which mediates the degradation of SMAD2. Inhibition of USP7 protected against proteotoxicity in mammalian neurons, and SMAD2 was found to be dysregulated in the nervous systems of ALS patients. These findings reveal a regulatory pathway of protein quality control that is implicated in the proteotoxicity-associated neurodegenerative diseases.
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spelling pubmed-76680972020-11-27 USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway Zhang, Tao Periz, Goran Lu, Yu-Ning Wang, Jiou Proc Natl Acad Sci U S A Biological Sciences An imbalance in cellular homeostasis occurring as a result of protein misfolding and aggregation contributes to the pathogeneses of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we report the identification of a ubiquitin-specific protease, USP7, as a regulatory switch in a protein quality-control system that defends against proteotoxicity. A genome-wide screen in a Caenorhabditis elegans model of SOD1-linked ALS identified the USP7 ortholog as a suppressor of proteotoxicity in the nervous system. The actions of USP7 orthologs on misfolded proteins were found to be conserved in Drosophila and mammalian cells. USP7 acts on protein quality control through the SMAD2 transcription modulator of the transforming growth factor β pathway, which activates autophagy and enhances the clearance of misfolded proteins. USP7 deubiquitinates the E3 ubiquitin ligase NEDD4L, which mediates the degradation of SMAD2. Inhibition of USP7 protected against proteotoxicity in mammalian neurons, and SMAD2 was found to be dysregulated in the nervous systems of ALS patients. These findings reveal a regulatory pathway of protein quality control that is implicated in the proteotoxicity-associated neurodegenerative diseases. National Academy of Sciences 2020-11-10 2020-10-26 /pmc/articles/PMC7668097/ /pubmed/33106424 http://dx.doi.org/10.1073/pnas.2014349117 Text en Copyright © 2020 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Zhang, Tao
Periz, Goran
Lu, Yu-Ning
Wang, Jiou
USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway
title USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway
title_full USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway
title_fullStr USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway
title_full_unstemmed USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway
title_short USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway
title_sort usp7 regulates als-associated proteotoxicity and quality control through the nedd4l–smad pathway
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668097/
https://www.ncbi.nlm.nih.gov/pubmed/33106424
http://dx.doi.org/10.1073/pnas.2014349117
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