Kouloulia, S;
Hallin, EI;
Simbriger, K;
Amorim, IES;
Lach, G;
Amvrosiadis, T;
Chalkiadaki, K;
... Gkogkas, CG; + view all
(2019)
Raptor-Mediated Proteasomal Degradation of Deamidated 4E-BP2 Regulates Postnatal Neuronal Translation and NF-kappa B Activity.
Cell Reports
, 29
(11)
3620-3635.e7.
10.1016/j.celrep.2019.11.023.
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Abstract
Summary: The translation initiation repressor 4E-BP2 is deamidated in the brain on asparagines N99/N102 during early postnatal brain development. This post-translational modification enhances 4E-BP2 association with Raptor, a central component of mTORC1 and alters the kinetics of excitatory synaptic transmission. We show that 4E-BP2 deamidation is neuron specific, occurs in the human brain, and changes 4E-BP2 subcellular localization, but not its disordered structure state. We demonstrate that deamidated 4E-BP2 is ubiquitinated more and degrades faster than the unmodified protein. We find that enhanced deamidated 4E-BP2 degradation is dependent on Raptor binding, concomitant with increased association with a Raptor-CUL4B E3 ubiquitin ligase complex. Deamidated 4E-BP2 stability is promoted by inhibiting mTORC1 or glutamate receptors. We further demonstrate that deamidated 4E-BP2 regulates the translation of a distinct pool of mRNAs linked to cerebral development, mitochondria, and NF-κB activity, and thus may be crucial for postnatal brain development in neurodevelopmental disorders, such as ASD.
| Type: | Article |
|---|---|
| Title: | Raptor-Mediated Proteasomal Degradation of Deamidated 4E-BP2 Regulates Postnatal Neuronal Translation and NF-kappa B Activity |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.celrep.2019.11.023 |
| Publisher version: | https://doi.org/10.1016/j.celrep.2019.11.023 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Cell Biology, INITIATION-FACTOR 4E, SYNAPTIC PLASTICITY, PROTEIN-SYNTHESIS, MAMMALIAN TARGET, REPRESSOR 4E-BP2, MICE LACKING, PHOSPHORYLATION, MTORC1, MACROMOLECULES, MECHANISMS |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10089961 |
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