2. Academic Validation
  3. 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

  • Mol Cell. 2015 Sep 17;59(6):956-69. doi: 10.1016/j.molcel.2015.07.033.
Yi-Heng Hao 1,  Michael D Fountain Jr 2,  Klementina Fon Tacer 1,  Fan Xia 3,  Weimin Bi 3,  Sung-Hae L Kang 3,  Ankita Patel 3,  Jill A Rosenfeld 4,  Cédric Le Caignec 5,  Bertrand Isidor 5,  Ian D Krantz 6,  Sarah E Noon 7,  Jean P Pfotenhauer 8,  Thomas M Morgan 8,  Rocio Moran 9,  Robert C Pedersen 10,  Margarita S Saenz 11,  Christian P Schaaf 12,  Patrick Ryan Potts 13
Affiliations

Affiliations

  • 1 Departments of Physiology, Pharmacology, and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2 Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
  • 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 4 Signature Genomics, Spokane, WA 99207, USA.
  • 5 Service de Génétique Médicale, CHU de Nantes, Nantes 44093, France.
  • 6 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 7 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 8 Division of Medical Genetics and Genomic Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 9 Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 10 Department of Pediatrics, Tripler Army Medical Center, Honolulu, HI 96859, USA.
  • 11 Clinical Genetics and Metabolism, Children's Hospital Colorado, Aurora, CO 80045, USA.
  • 12 Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: [email protected].
  • 13 Departments of Physiology, Pharmacology, and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
PMID: 26365382 DOI: 10.1016/j.molcel.2015.07.033
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.

Figures