Stella Kouloulia, Erik I. Hallin, Konstanze Simbriger, Inês S. Amorim, Gilliard Lach, Theoklitos Amvrosiadis, Kleanthi Chalkiadaki, Agniete Kampaite, Vinh Tai Truong, Mehdi Hooshmandi, Seyed Mehdi Jafarnejad, Paul Skehel, Petri Kursula, Arkady Khoutorsky, Christos G. Gkogkas, Raptor-Mediated Proteasomal Degradation of Deamidated 4E-BP2 Regulates Postnatal Neuronal Translation and NF-κB Activity, Cell Reports, Volume 29, Issue 11, 2019, Pages 3620-3635.e7, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2019.11.023
Raptor-mediated proteasomal degradation of deamidated 4E-BP2 regulates postnatal neuronal translation and NF-κB activity
|Author:||Kouloulia, Stella1; Hallin, Erik I.2; Simbriger, Konstanze1;|
1Centre for Discovery Brain Sciences and Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK
2Department of Biomedicine, University of Bergen, Bergen N-5020, Norway
3Department of Anesthesia and Alan Edwards Centre for Research on Pain, McGill University, Montréal H3A 0G1, QC, Canada
4Centre for Cancer Research and Cell Biology, Queen’s University of Belfast, Belfast BT9 7AE, UK
5Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu FI-90014, Finland
6Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh EH8 9XD, UK
|Online Access:||PDF Full Text (PDF, 5.6 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe202002256420
|Publish Date:|| 2020-02-25
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 of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This work was supported by grants to C.G.G.: Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society (107687/Z/15/Z) and a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator grant from the Brain & Behavior Research Foundation (24968).
© 2019 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).