USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder PMID: 26365382

ADC Targets in Oncology

2026-04-10

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

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].

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.