La mutation U3 de l'Ubiquitine Ligase liée à l'autisme active la voie Wnt / β-caténine en inhibant le protéasome

Aperçu: G.M.

UBE3A est une ubiquite ligase (enzyme),  partie de HECT E3 dont le dysfonctionnement est lié à l'autisme, au syndrome d'Angelman et au cancer. 

Récemment, l'équipe a mis en évidence un mutant UBE3A nouvellement lié au autisme (UBE3AT485A) qui perturbe le contrôle de la phosphorylation de l'activité UBE3A.  

Dans l'ensemble, les résultats indiquent que UBE3A régule la signalisation Wnt d'une manière dépendante du contexte cellulaire et qu'une mutation liée à l'autisme exacerbe ces effets de signalisation. 

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J Biol Chem. 2017 May 30. pii: jbc.M117.788448. doi: 10.1074/jbc.M117.788448.

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

Yi JJ¹, Paranjape SR², Walker MP², Choudhury R², Wolter JM², Fragola G², Emanuele MJ², Major MB², Zylka MJ³.

Author information

1

Washington University School of Medicine, United States.

2

The University of North Carolina at Chapel Hill, United States.

3

The University of North Carolina at Chapel Hill, United States zylka@med.unc.edu

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 suggest that dysfunctional UBE3A might affect additional proteins and pathways that are sensitive to proteasome activity.

Copyright © 2017, The American Society for Biochemistry and Molecular Biology.

KEYWORDS:

E6-AP; UBE3A; Wnt signaling; autism; beta-catenin (B-catenin ); proteasome; proteomics

PMID: 28559284

DOI: 10.1074/jbc.M117.788448