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.

由于蛋白质错误折叠和聚集而导致的细胞稳态失衡是神经退行性疾病，包括肌萎缩性侧索硬化症（ALS）的致病菌。在这里，我们报告了泛素特异性蛋白酶USP7的鉴定，它是防御蛋白质毒性的蛋白质质量控​​制系统中的调控开关。在与SOD1连接的ALS的秀丽隐杆线虫模型中进行的全基因组筛选将USP7直向同源物鉴定为神经系统蛋白毒性的抑制剂。发现果蝇中USP7直向同源物对错误折叠的蛋白质的作用是保守的和哺乳动物细胞。USP7通过转化生长因子β途径的SMAD2转录调节剂作用于蛋白质质量控​​制，该途径激活自噬并增强错误折叠的蛋白质的清除率。USP7泛素化E3泛素连接酶NEDD4L，介导SMAD2的降解。USP7的抑制作用可防止哺乳动物神经元发生蛋白毒性，并且发现SMA患者的神经系统中SMAD2失调。这些发现揭示了蛋白质质量控​​制的调节途径，该途径与蛋白毒性相关的神经退行性疾病有关。