@article{8ec747a514fa43fbb0c2bb8dc4d3c995,
title = "USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder",
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. Hao et al. describe a function of the USP7 deubiquitinating enzyme in regulation of WASH/retromer-mediated endosomal protein recycling. USP7 functions as a molecular rheostat to prevent auto-ubiquitination and proteasomal degradation of TRIM27 E3 ubiquitin ligase, but also deubiquitinates WASH. Genetic studies identify cases of USP7 mutation/deletion resulting in a human neurodevelopmental disorder that overlaps with MAGE-L2 mutation.",
author = "Hao, {Yi Heng} and Fountain, {Michael D.} and {Fon Tacer}, Klementina and Fan Xia and Weimin Bi and Kang, {Sung Hae L} and Ankita Patel and Rosenfeld, {Jill A.} and {Le Caignec}, C{\'e}dric and Bertrand Isidor and Krantz, {Ian D.} and Noon, {Sarah E.} and Pfotenhauer, {Jean P.} and Morgan, {Thomas M.} and Rocio Moran and Pedersen, {Robert C.} and Saenz, {Margarita S.} and Schaaf, {Christian P.} and Potts, {Patrick Ryan}",
note = "Funding Information: We are indebted to the patients and their families for their willingness to participate in our study. This study makes use of data generated by the DECIPHER Consortium. A full list of centers that contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk . Funding for the project was provided by the Wellcome Trust. Those who carried out the original analysis and collection of the data for DECIPHER bear no responsibility for the further analysis or interpretation of it by our group or the registered users of DECIPHER. Funding Information: We thank members of the P.R.P. lab, Michael Rosen, Daniel Billadeau, and Ezra Burstein for helpful discussions and critical reading of the manuscript. We also thank Pamela Mellon and Bert Vogelstein for critical reagents, Genevera I. Allen for statistical support and discussion, and Pawel Stankiewicz for his invaluable contributions on patient data. This work was supported by Michael L. Rosenberg Scholar in Medical Research fund (to P.R.P.), CPRIT R1117 (to P.R.P.), WELCH Foundation I-1821 (to P.R.P.), NIH R01GM111332 (to P.R.P.), the Joan and Stanford Alexander Family (to C.P.S.), and the Foundation for Prader-Willi Research (to C.P.S. and P.R.P.). The project was supported in part by IDDRC grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. Cores: Translational Core. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",
year = "2015",
month = sep,
day = "17",
doi = "10.1016/j.molcel.2015.07.033",
language = "English (US)",
volume = "59",
pages = "956--969",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}