USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder.
USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder.
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DOI：
10.1016/j.molcel.2015.07.033
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发表时间：
2015-09-17
期刊：
影响因子：
16
通讯作者：
Potts PR
中科院分区：
文献类型：
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作者：
Hao YH;Fountain MD Jr;Fon Tacer K;Xia F;Bi W;Kang SH;Patel A;Rosenfeld JA;Le Caignec C;Isidor B;Krantz ID;Noon SE;Pfotenhauer JP;Morgan TM;Moran R;Pedersen RC;Saenz MS;Schaaf CP;Potts PR
内体蛋白再循环是一个基本的细胞过程，对细胞稳态、信号传导和命运决定很重要，与多种疾病有关。WASH是该过程所必需的肌动蛋白成核蛋白，其活性通过MAGE-L2-TRIM 27泛素连接酶的K63连接的泛素化来控制。在这里，我们表明，USP 7去泛素化酶是MAGE-L2-TRIM 27连接酶的组成部分，是必不可少的Wash介导的内体肌动蛋白组装和蛋白质回收。从机制上讲，USP 7作为一种分子变阻器，通过抵消TRIM 27自身泛素化/降解和通过直接去泛素化防止WASH过度激活来精确微调内体F-肌动蛋白水平。重要的是，我们确定了患有神经发育障碍的个体中USP 7的从头杂合功能丧失突变，其特征是智力残疾和自闭症谱系障碍。这些结果为内体运输提供了意想不到的见解，阐明了泛素连接酶和去泛素化酶之间的协同性，并建立了USP 7在人类神经发育疾病中的作用。
Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin nucleating protein essential for this process and its activity is controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show that the USP7 deubiquitinating enzyme is an integral component of the MAGE-L2-TRIM27 ligase and is essential for WASH-mediated endosomal actin assembly and protein recycling. Mechanistically, USP7 acts as a molecular rheostat to precisely fine-tune endosomal F-actin levels by counteracting TRIM27 auto-ubiquitination/degradation and preventing overactivation of WASH through directly deubiquitinating it. Importantly, we identify de novo heterozygous loss-of-function mutations of USP7 in individuals with a neurodevelopmental disorder, featuring intellectual disability and autism spectrum disorder. These results provide unanticipated insights into endosomal trafficking, illuminate the cooperativity between a ubiquitin ligase and a deubiquitinating enzyme, and establish a role for USP7 in human neurodevelopmental disease.