USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L-SMAD pathway.
USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L-SMAD pathway.
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DOI：
10.1073/pnas.2014349117
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发表时间：
2020-11-10
影响因子：
11.1
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Zhang T;Periz G;Lu YN;Wang J
蛋白质稳态是所有活细胞功能的基础。内稳态的扰动或蛋白毒性在肌萎缩侧索硬化症和相关神经退行性疾病的发病机制中起重要作用。为了防止蛋白质毒性，细胞已经进化出复杂的质量控制机制，这些机制可以进行适应，包括增强错误折叠蛋白质的周转。然而，质量控制系统是如何通过更高层次的监管途径进行协调的还没有完全了解。我们发现了一种独特的蛋白毒性抑制剂，泛素特异性蛋白酶USP7，其作用从无脊椎动物到哺乳动物系统都是保守的，并由涉及NEDD4L和SMAD2的底物级联介导。这些发现揭示了一种以前未知的蛋白质质量控制调控途径，并为神经退行性疾病的干预措施提供了新的策略。由于蛋白质错误折叠和聚集而发生的细胞内稳态失衡有助于神经退行性疾病（包括肌萎缩性侧索硬化症（ALS））的发病机制。在这里，我们报告了一个泛素特异性蛋白酶，USP7，作为一个调节开关的蛋白质质量控制系统，抵御蛋白毒性的鉴定。在SOD 1相关ALS的秀丽隐杆线虫模型中进行的全基因组筛选将USP 7直系同源物鉴定为神经系统中蛋白毒性的抑制剂。发现USP7直系同源物对错误折叠蛋白的作用在果蝇和哺乳动物细胞中是保守的。USP7通过转化生长因子β途径的SMAD 2转录调节剂作用于蛋白质质量控制，其激活自噬并增强错误折叠蛋白质的清除。USP7使E3泛素连接酶NEDD4L去泛素化，其介导SMAD2的降解。USP7的抑制保护了哺乳动物神经元中的蛋白毒性，并且发现SMAD2在ALS患者的神经系统中失调。这些发现揭示了蛋白质质量控制的调节途径，其与蛋白质毒性相关的神经退行性疾病有关。
Protein homeostasis is fundamental to the functioning of all living cells. Perturbation of the homeostasis, or proteotoxicity, plays an important role in the pathogenesis of amyotrophic lateral sclerosis and related neurodegenerative diseases. To guard against proteotoxicity, cells have evolved sophisticated quality-control mechanisms that make adaptations including enhanced turnover of misfolded proteins. However, how the quality-control systems are coordinated through higher-order regulatory pathways is not fully understood. We have discovered a unique suppressor of proteotoxicity, the ubiquitin-specific protease USP7, whose action is conserved from invertebrate to mammalian systems and mediated by a substrate cascade involving NEDD4L and SMAD2. These findings reveal a previously unknown regulatory pathway for protein quality control and provide new strategies for developing interventions for neurodegenerative diseases. 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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影响因子：
14.8
作者：
Barmada, Sami J.;Serio, Andrea;Arjun, Arpana;Bilican, Bilada;Daub, Aaron;Ando, D. Michael;Tsvetkov, Andrey;Pleiss, Michael;Li, Xingli;Peisach, Daniel;Shaw, Christopher;Chandran, Siddharthan;Finkbeiner, Steven
通讯作者：
Finkbeiner, Steven
影响因子：
2.5
作者：
Nguyen DKH;Thombre R;Wang J
通讯作者：
Wang J
影响因子：
4.7
作者：
Gal J;Ström AL;Kwinter DM;Kilty R;Zhang J;Shi P;Fu W;Wooten MW;Zhu H
通讯作者：
Zhu H
影响因子：
29
作者：
Heimbucher T;Liu Z;Bossard C;McCloskey R;Carrano AC;Riedel CG;Tanasa B;Klammt C;Fonslow BR;Riera CE;Lillemeier BF;Kemphues K;Yates JR 3rd;O'Shea C;Hunter T;Dillin A
通讯作者：
Dillin A
影响因子：
14.9
作者：
Dereeper A;Guignon V;Blanc G;Audic S;Buffet S;Chevenet F;Dufayard JF;Guindon S;Lefort V;Lescot M;Claverie JM;Gascuel O
通讯作者：
Gascuel O