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 10;59(6):956-69. Epub 2015 Sep 10.

Departments of Physiology, Pharmacology, and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

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.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molcel.2015.07.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575888PMC
September 2015
29 Reads

Publication Analysis

Top Keywords

protein recycling
12
usp7 acts
8
deubiquitinating enzyme
8
endosomal protein
8
neurodevelopmental disorder
8
human neurodevelopmental
8
acts molecular
8
molecular rheostat
8
ubiquitin ligase
8
usp7
5
endosomal
5
preventing overactivation
4
enzyme integral
4
component mage-l2-trim27
4
mage-l2-trim27 ligase
4
integral component
4
insights endosomal
4
usp7 deubiquitinating
4
auto-ubiquitination/degradation preventing
4
ligase essential
4

Similar Publications