Raptor-Mediated Proteasomal Degradation of Deamidated 4E-BP2 Regulates Postnatal Neuronal Translation and NF-κB Activity.
Cell Rep
; 29(11): 3620-3635.e7, 2019 Dec 10.
Article
em En
| MEDLINE
| ID: mdl-31825840
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
NF-kappa B
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Fatores de Iniciação em Eucariotos
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Complexo de Endopeptidases do Proteassoma
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Proteína Regulatória Associada a mTOR
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Neurônios
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Reino Unido