USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder

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

Research output: Contribution to journalArticlepeer-review

121 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)956-969
Number of pages14
JournalMolecular cell
Issue number6
StatePublished - Sep 17 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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