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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2020
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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. |
format | Online Article Text |
id | pubmed-7668097 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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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