TY - JOUR TI - UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity AU - Sun, Jiandong AU - Liu, Yan AU - Jia, Yousheng AU - Hao, Xiaoning AU - Lin, Wei ju AU - Tran, Jennifer AU - Lynch, Gary AU - Baudry, Michel AU - Bi, Xiaoning A2 - Sonenberg, Nahum A2 - Zoghbi, Huda Y VL - 7 PY - 2018 DA - 2018/07/18 SP - e37993 C1 - eLife 2018;7:e37993 DO - 10.7554/eLife.37993 UR - https://doi.org/10.7554/eLife.37993 AB - 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. KW - Angelman syndrome KW - arc KW - LTP KW - lysosome KW - proteasome KW - protein synthesis JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -