The translation initiation repressor 4E-BP2 is deamidated in 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 human brain and changes 4E-BP2 subcellular localisation, 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 AMPARs, but not NMDARs. 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.
Kouloulia, Stella and Ingmar-Hallin, Erik and Simbriger, Konstanze and Amorim, Ines S. and Lach, Gilliard and Amvrosiadis, Theoklitos and Kampaite, Agniete and Jafarnejad, Seyed Mehdi and Truong, Vinh Tai and Hooshmandi, Mehdi and Skehel, Paul and Kursula, Petri and Khoutorsky, Arkady and Khoutorsky, Arkady and Gkogkas, Christos, Raptor-Mediated Proteasomal Degradation of Deamidated 4E-BP2 Regulates Postnatal Neuronal Translation and NF-Kappa B Activity (May 30, 2019). Available at SSRN: https://ssrn.com/abstract=3396492 or http://dx.doi.org/10.2139/ssrn.3396492
This version of the paper has not been formally peer reviewed.
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