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.
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
