Raptor-Mediated Proteasomal Degradation of Deamidated 4E-BP2 Regulates Postnatal Neuronal Translation and NF-Kappa B Activity
56 Pages Posted: 31 May 2019 Sneak Peek Status: Review CompleteMore...
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.
Keywords: Asparagine deamidation, Translational control, Postnatal brain, 4E-BP2, Raptor, CUL4B, Proteasome, NF-kappa B, mTORC1
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