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

Abstract

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.

An Integrative Transcriptome-Wide Analysis of Amyotrophic Lateral Sclerosis for the Identification of Potential Genetic Markers and Drug Candidates

“…Inhibition of USP37 was reported to facilitate the proteasomal clearance of neurotoxic proteins [ 54 ]. Acting in a similar biological mechanism to USP37 , USP7 was suggested to be involved in the etiology of ALS associated with proteotoxicity [ 55 ]. In light of these facts, we suggest that our TWAS successfully identified biologically interpretable novel genes implicated in the pathogenesis of ALS.…”

Deubiquitinases in Neurodegeneration

“…To counter the effects of proteotoxicity, organisms have evolved elaborate quality-control mechanisms to remove misfolded and aggregated proteins [133,134]. USP7 is a suppressor of proteotoxicity [135]. The transforming growth factor (TGF) β-mothers against decapentaplegic homolog (SMAD) pathway is involved in protein quality control and mediates USP7 s effects on the clearance of misfolded proteins [135].…”

“…USP7 is a suppressor of proteotoxicity [135]. The transforming growth factor (TGF) β-mothers against decapentaplegic homolog (SMAD) pathway is involved in protein quality control and mediates USP7 s effects on the clearance of misfolded proteins [135]. USP7 deubiquitinates NEDD4 like E3 ubiquitin protein ligase, which ubiquitinates SMAD2, and influences the SMAD-mediated transcriptional activity that promotes protein quality control [136].…”

“…USP7 deubiquitinates NEDD4 like E3 ubiquitin protein ligase, which ubiquitinates SMAD2, and influences the SMAD-mediated transcriptional activity that promotes protein quality control [136]. Furthermore, high SMAD2 levels are found in the tissues of patients with ALS, suggesting that defects in this protein quality control pathway are involved in its pathophysiology [135,137]. USP7 also interacts with ATXN1, which is associated with spinocerebellar ataxia type 1 (SCA1), an autosomal dominant neurodegenerative disorder characterized by several neurological defects and symptoms [91].…”

ARV-771 Acts as an Inducer of Cell Cycle Arrest and Apoptosis to Suppress Hepatocellular Carcinoma Progression

“…Protein stability control is mainly maintained by the balance between ubiquitination and deubiquitination. Unbalanced state of ubiquitination and deubiquitination has been proposed to involve in or even dominate the development and progression of various diseases, such as cancers ( Liao et al, 2017 ; Liao et al, 2018 ; Yu et al, 2021 ), cardiovascular diseases ( Qi et al, 2020 ; Rangrez et al, 2020 ) and neurodegenerative diseases ( Zhang et al, 2020 ; Liu and Moussa 2021 ). Protein deubiquitination, a biological process in reverse to protein ubiquitination, is regulated by a class of deubiquitinases (DUBs) which contain a special deubiquitinating domain.…”