Format

Send to

Choose Destination
J Biol Chem. 2017 Jul 28;292(30):12503-12515. doi: 10.1074/jbc.M117.788448. Epub 2017 May 30.

The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/β-catenin pathway by inhibiting the proteasome.

Author information

1
From the Department of Neuroscience, Washington University School of Medicine, Saint Louis, Missouri 63110 and.
2
Department of Cell Biology and Physiology.
3
UNC Neuroscience Center.
4
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599.
5
Department of Pharmacology, and.
6
Department of Cell Biology and Physiology, zylka@med.unc.edu.
7
Carolina Institute for Developmental Disabilities.

Abstract

UBE3A is a HECT domain E3 ubiquitin ligase whose dysfunction is linked to autism, Angelman syndrome, and cancer. Recently, we characterized a de novo autism-linked UBE3A mutant (UBE3AT485A) that disrupts phosphorylation control of UBE3A activity. Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A. We also found that UBE3AT485A activates Wnt signaling to a greater extent in cells with low levels of ongoing Wnt signaling, suggesting that cells with low basal Wnt activity are particularly vulnerable to UBE3AT485A mutation. Ligase-dead UBE3A did not stimulate Wnt pathway activation. Overexpression of several proteasome subunits reversed the effect of UBE3AT485A on Wnt signaling. We also observed that subunits that interact with UBE3A and affect Wnt signaling are located along one side of the 19S regulatory particle, indicating a previously unrecognized spatial organization to the proteasome. Altogether, our findings indicate that UBE3A regulates Wnt signaling in a cell context-dependent manner and that an autism-linked mutation exacerbates these signaling effects. Our study has broad implications for human disorders associated with UBE3A gain or loss of function and suggests that dysfunctional UBE3A might affect additional proteins and pathways that are sensitive to proteasome activity.

KEYWORDS:

E6-AP; UBE3A; Wnt signaling; autism; proteasome; proteomics; β-catenin

PMID:
28559284
PMCID:
PMC5535025
DOI:
10.1074/jbc.M117.788448
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center