Title |
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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Published in |
Molecular Cell, September 2015
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DOI | 10.1016/j.molcel.2015.07.033 |
Pubmed ID | |
Authors |
Yi-Heng Hao, Michael D. Fountain, Klementina Fon Tacer, Fan Xia, Weimin Bi, Sung-Hae L. Kang, Ankita Patel, Jill A. Rosenfeld, Cédric Le Caignec, Bertrand Isidor, Ian D. Krantz, Sarah E. Noon, Jean P. Pfotenhauer, Thomas M. Morgan, Rocio Moran, Robert C. Pedersen, Margarita S. Saenz, Christian P. Schaaf, Patrick Ryan Potts |
Abstract |
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 an ubiquitin ligase and a deubiquitinating enzyme, and establish a role for USP7 in human neurodevelopmental disease. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Unknown | 2 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 2 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
India | 2 | 1% |
United Kingdom | 1 | <1% |
Unknown | 195 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 48 | 24% |
Researcher | 27 | 14% |
Student > Bachelor | 19 | 10% |
Student > Master | 15 | 8% |
Professor | 8 | 4% |
Other | 26 | 13% |
Unknown | 55 | 28% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 67 | 34% |
Agricultural and Biological Sciences | 29 | 15% |
Neuroscience | 21 | 11% |
Medicine and Dentistry | 10 | 5% |
Chemistry | 5 | 3% |
Other | 9 | 5% |
Unknown | 57 | 29% |