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.
authors.affiliation: Departments of Physiology, Pharmacology, and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yi-Heng
authors.initials: YH
authors.lastname: Hao
authors.affiliation: 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.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Fountain
authors.affiliation: Departments of Physiology, Pharmacology, and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Klementina
authors.initials: K
authors.lastname: Fon Tacer
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sung-Hae L
authors.initials: SH
authors.lastname: Kang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.affiliation: Signature Genomics, Spokane, WA 99207, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Service de Génétique Médicale, CHU de Nantes, Nantes 44093, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Le Caignec
authors.affiliation: Service de Génétique Médicale, CHU de Nantes, Nantes 44093, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Noon
authors.affiliation: Division of Medical Genetics and Genomic Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Jean P
authors.initials: JP
authors.lastname: Pfotenhauer
authors.affiliation: Division of Medical Genetics and Genomic Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Morgan
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Rocio
authors.initials: R
authors.lastname: Moran
authors.affiliation: Department of Pediatrics, Tripler Army Medical Center, Honolulu, HI 96859, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Pedersen
authors.affiliation: Clinical Genetics and Metabolism, Children's Hospital Colorado, Aurora, CO 80045, USA.
authors.forename: Margarita S
authors.initials: MS
authors.lastname: Saenz
authors.affiliation: 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: schaaf@bcm.edu.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Schaaf
authors.affiliation: Departments of Physiology, Pharmacology, and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: ryan.potts@utsouthwestern.edu.
authors.forename: Patrick Ryan
authors.initials: PR
authors.lastname: Potts
mesh_terms: D000293:Adolescent; D000067877:Autism Spectrum Disorder / Q000201:enzymology* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D025461:Feedback, Physiological; D005260:Female; D045325:HCT116 Cells; D057895:Haploinsufficiency; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D008607:Intellectual Disability / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology; D009687:Nuclear Proteins / Q000378:metabolism; D021381:Protein Transport; D059748:Proteolysis; D017384:Sequence Deletion; D043222:Ubiquitin Thiolesterase / Q000502:physiology*; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination; D000070584:Tripartite Motif Proteins
chemical_list: D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; C064419:TRIM27 protein, human; D000070584:Tripartite Motif Proteins; C549919:WASH protein, human; C464569:USP7 protein, human