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

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An imbalance in cellular homeostasis occurring as a result of protein misfolding and aggregation contributes to the pathogen-eses 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.

Original languageEnglish (US)
Pages (from-to)28114-28125
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number45
StatePublished - Nov 10 2020


  • Protein misfolding | USP7 | NEDD4L | SMAD | protein quality control

ASJC Scopus subject areas

  • General


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