Raptor-Mediated Proteasomal Degradation of Deamidated 4E-BP2 Regulates Postnatal Neuronal Translation and NF-κB Activity

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. : Kouloulia et al. demonstrate that, during early postnatal brain development, deamidation of the translation initiation factor 4E-BP2 renders it susceptible to ubiquitination and proteasomal degradation via enhanced binding to the Raptor-CUL4B complex. mTORC1 or glutamate receptor inhibition stabilizes deamidated 4E-BP2. Moreover, deamidated 4E-BP2 regulates the translation of specific mRNAs and NF-κB activity. Keywords: asparagine deamidation, translational control, postnatal brain, 4E-BP2, Raptor, CUL4B, proteasome, NF-κB, mTORC1