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

• DOI: 10.1016/j.molcel.2015.07.033
• Publication Date: 2015-09-12T05:10:29Z
• Authors: 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
• Keywords: Deubiquitinating enzyme; Ubiquitin-Protein Ligases; HEK 293 cells; ESCRT

Endosomal protein recycling is a fundamental cellular process important for homeostasis, signaling, and fate determination that implicated in several diseases. WASH an actin-nucleating essential this process, its activity controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show USP7 deubiquitinating enzyme integral component of ligase WASH-mediated endosomal actin assembly recycling. Mechanistically, acts as molecular rheostat to precisely fine-tune F-actin levels counteracting TRIM27 auto-ubiquitination/degradation preventing overactivation directly it. Importantly, identify de novo heterozygous loss-of-function mutations individuals with neurodevelopmental disorder, featuring intellectual disability autism spectrum disorder. These results provide unanticipated insights into trafficking, illuminate cooperativity between enzyme, establish role human disease.