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.
Highlights
The mechanistic target of rapamycin is a highly conserved and ubiquitously expressed protein kinase complex, which plays important roles in cell survival, growth, and metabolism. mTOR, consists of two complexes, mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2, which integrate extracellular signals with intracellular energy levels and cellular stress status to regulate many important cellular functions (Laplante and Sabatini, 2012; Takei and Nawa, 2014)
Our results provide several lines of evidence indicating that Ube3a is an E3 ligase for p18, and that Ube3a-mediated p18 ubiquitination leads to its degradation by the proteasome
Our results showed for the first time that, in hippocampal neurons, p18 is essential for lysosomal localization of other Ragulator members and Rag guanosine triphosphatases (GTPases), as p18 KD markedly reduced the lysosomal localization of these proteins, which is in agreement with that reported in other cell types (Nada et al, 2009; Sancak et al, 2010)
Summary
The mechanistic target of rapamycin (mTOR) is a highly conserved and ubiquitously expressed protein kinase complex, which plays important roles in cell survival, growth, and metabolism. mTOR, consists of two complexes, mTORC1 and mTORC2, which integrate extracellular signals (growth factors, neurotransmitters, nutrients, etc.) with intracellular energy levels and cellular stress status to regulate many important cellular functions (Laplante and Sabatini, 2012; Takei and Nawa, 2014). The E3 ligase responsible for p18 ubiquitination was not identified It is not known whether the Ragulator-Rag complex regulates mTORC1 in the central nervous system (CNS) in a way similar to that in peripheral tissues. Inhibition of mTORC1 by rapamycin treatment reduced mTORC1 activity and normalized mTORC2 activity, suggesting that mTORC1 over-activation is the trigger for alterations in mTOR signaling in AS mice It remains unknown how Ube3a deficiency results in mTORC1 over-activation. In the absence of Ube3a, p18 accumulates in neurons, resulting in mTORC1 over-activation, abnormal synaptic morphology, and impaired synaptic plasticity and learning. These findings reveal a previously unidentified regulatory mechanism for mTORC1 activation and suggest potential therapeutic targets for cognitive disorders associated with abnormal mTORC1 signaling
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