USP7 acts as a molecular rheostat to promote WASH-dependent endosomal protein recycling and is mutated in a human neurodevelopmental disorder.
Open accessAbstract
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.
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Heterozygous loss-of-function USP7 mutations have been identified in 23 individuals, all of whom have neurodevelopmental disorders and physical characteristics including dysmorphic facial features.
“Heterozygous loss-of-function USP7 mutations have, however, been identified in 23 individuals, all of whom have experienced neurodevelopmental disorders – characterized by developmental delay/intellectual disability (DD/ID), speech delay, behavioral anomalies and autism spectrum disorder – as well as physical characteristics that include dysmorphic facial features (Hao et al., 2015; Fountain et al”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Hao et al., 2015
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“Heterozygous loss-of-function USP7 mutations have, however, been identified in 23 individuals, all of whom have experienced neurodevelopmental disorders – characterized by developmental delay/intellectual disability (DD/ID), speech delay, behavioral anomalies and autism spectrum disorder – as well as physical characte…”
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- Authors
- Hao, Y.-H., Fountain, M. D., Fon Tacer, K., Xia, F., Bi, W., Kang, S.-H. L., Patel, A., Rosenfeld, J. A., Le Caignec, C., Isidor, B., Krantz, I. D., Noon, S. E., Pfotenhauer, J. P., Morgan, T. M., Moran, R., Pedersen, R. C., Saenz, M. S., Schaaf, C. P., & Potts, P. R.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Baylor College of Medicine (US)
- Genome Canada (CA)
- Centre Hospitalier Universitaire de Nantes (FR)
- Children's Hospital of Philadelphia (US)
- Vanderbilt University (US)
- Cleveland Clinic (US)
- Tripler Army Medical Center (US)
- Children's Hospital Colorado (US)
- Corresponding author
- Schaaf, Christian P.
- Potts, Patrick Ryan
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 59
- Issue
- 6
- Pages
- 956-969
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4575888
- OpenAlex
- W1843647340
- Cited by
- 206
- References
- 45
- Citations by year
- 2026: 18 · 2025: 17 · 2024: 16 · 2023: 13 · 2022: 24 · 2021: 22 · 2020: 23 · 2019: 20 · 2018: 20 · 2017: 23 · 2016: 10
- FWCI
- 7.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust
- National Institutes of Health
- Intellectual and Developmental Disabilities Research Center
- National Institute of General Medical Sciences (R01GM111332)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083092, P30HD024064)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- USP7, WASH complex, K63-linked ubiquitination, deubiquitination, actin nucleation, F-actin assembly, neurodevelopmental disorders, intellectual disability, autism spectrum disorder, endosomal trafficking
- MeSH terms
- Autism Spectrum Disorder, Tripartite Motif Proteins, Ubiquitin-Specific Peptidase 7, Adolescent, Child, Child, Preschool, DNA-Binding Proteins, Female, Humans, Hypothalamus, Male, Intellectual Disability, Microfilament Proteins, Neurons, Nuclear Proteins, Endosomes, Sequence Deletion, Protein Transport, Feedback, Physiological, Ubiquitin Thiolesterase, HCT116 Cells, Ubiquitination, Haploinsufficiency, Proteolysis
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