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Hao, Yi-Heng; Fountain, Michael D.; Fon Tacer, Klementina; Xia, Fan; Bi, Weimin; Kang, Sung-Hae L.; Patel, Ankita; Rosenfeld, Jill A.; Le Caignec, Cédric; Isidor, Bertrand; Krantz, Ian D.; Noon, Sarah E.; Pfotenhauer, Jean P.; Morgan, Thomas M.; Moran, Rocio; Pedersen, Robert C.; Saenz, Margarita S.; Schaaf, Christian P.; Potts, Patrick Ryan
Molecular cell, 09/2015, Volume: 59, Issue: 6Journal Article
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. Display omitted •USP7 is part of the MAGE-L2-TRIM27 ubiquitin ligase and enables endosomal recycling•USP7 protects TRIM27 from auto-ubiquitination and proteasomal degradation•USP7 buffers WASH ubiquitination levels to maintain proper endosomal actin levels•Mutation of USP7 causes a human neurodevelopmental syndrome, including autism 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.
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