UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity

ELife
Jiandong SunXiaoning Bi

Abstract

Accumulating evidence indicates that the lysosomal Ragulator complex is essential for full activation of the mechanistic target of rapamycin complex 1 (mTORC1). Abnormal mTORC1 activation has been implicated in several developmental neurological disorders, including Angelman syndrome (AS), which is caused by maternal deficiency of the ubiquitin E3 ligase UBE3A. Here we report that Ube3a regulates mTORC1 signaling by targeting p18, a subunit of the Ragulator. Ube3a ubiquinates p18, resulting in its proteasomal degradation, and Ube3a deficiency in the hippocampus of AS mice induces increased lysosomal localization of p18 and other members of the Ragulator-Rag complex, and increased mTORC1 activity. p18 knockdown in hippocampal CA1 neurons of AS mice reduces elevated mTORC1 activity and improves dendritic spine maturation, long-term potentiation (LTP), as well as learning performance. Our results indicate that Ube3a-mediated regulation of p18 and subsequent mTORC1 signaling is critical for typical synaptic plasticity, dendritic spine development, and learning and memory.

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Citations

Jun 12, 2019·Translational Psychiatry·J C LauterbornJ N Crawley
Feb 23, 2020·The FEBS Journal·Carina MarangaSimão Teixeira da Rocha
Dec 24, 2019·Journal of Neuroscience Research·Xin Yang
Dec 19, 2019·Frontiers in Molecular Neuroscience·Vipendra KumarNihar Ranjan Jana
Jan 9, 2021·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Ming-Chun HsiehHsien-Yu Peng
Mar 7, 2021·International Journal of Molecular Sciences·Shasha YinWenjian Gan
Mar 24, 2021·Biological Reviews of the Cambridge Philosophical Society·Yiwen WangBernard Moussian

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Methods Mentioned

BETA
GTPases
ubiquitination
pull-down
transfection
myristoylation
density gradient centrifugation
immunoprecipitation
immunoprecipitation assay
co-immunoprecipitation assay
GTPase

Software Mentioned

pCLAMP
VectorBuilder
Accell
Origin
GraphPad Prism
Freezeframe
Freezeview
ImageJ
Mini Analysis Program
Clampex

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