Raptor-Mediated Proteasomal Degradation of Deamidated 4E-BP2 Regulates Postnatal Neuronal Translation and NF-?B Activity.
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-?B activity, and thus may be crucial for postnatal brain development in neurodevelopmental disorders, such as ASD.
Mesh Terms:
Animals, Brain, Cells, Cultured, Cullin Proteins, Eukaryotic Initiation Factors, Female, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, NF-kappa B, Neurons, Proteasome Endopeptidase Complex, Protein Binding, Proteolysis, Regulatory-Associated Protein of mTOR
Animals, Brain, Cells, Cultured, Cullin Proteins, Eukaryotic Initiation Factors, Female, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, NF-kappa B, Neurons, Proteasome Endopeptidase Complex, Protein Binding, Proteolysis, Regulatory-Associated Protein of mTOR
Cell Rep
Date: Dec. 10, 2019
PubMed ID: 31825840
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