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Raptor-Mediated Proteasomal Degradation of Deamidated 4E-BP2 Regulates Postnatal Neuronal Translation and NF-κB Activity
- Source :
- Cell Reports, Kouloulia, S, Hallin, E I, Simbriger, K, Amorim, I S, Lach, G, Amvrosiadis, T, Chalkiadaki, K, Kampaite, A, Truong, V T, Hooshmandi, M, Jafarnejad, S M, Skehel, P, Kursula, P, Khoutorsky, A & Gkogkas, C G 2019, ' Raptor-Mediated Proteasomal Degradation of Deamidated 4E-BP2 Regulates Postnatal Neuronal Translation and NF-κB Activity ', Cell Reports, vol. 29, no. 11, pp. 3620-3635.e7 . https://doi.org/10.1016/j.celrep.2019.11.023, Cell reports, Cell Reports, Vol 29, Iss 11, Pp 3620-3635.e7 (2019), 'Cell Reports ', vol: 29, pages: 3620-3635 (2019)
- Publication Year :
- 2019
-
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.<br />Graphical Abstract<br />Highlights • Deamidated 4E-BP2 occurs in neurons and is susceptible to ubiquitination/degradation • mTORC1 or glutamate receptor inhibition stabilizes deamidated 4E-BP2 • A Raptor-CUL4B ubiquitin ligase complex binds to deamidated 4E-BP2 • Deamidated 4E-BP2 regulates postnatal brain translation and NF-κB activity<br />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.
- Subjects :
- 0301 basic medicine
Male
4E-BP2
asparagine deamidation
mTORC1
NF-κB
Mice
0302 clinical medicine
Ubiquitin
Eukaryotic Initiation Factors
lcsh:QH301-705.5
Cells, Cultured
Neurons
biology
Chemistry
Glutamate receptor
NF-kappa B
Brain
translational control
Translation (biology)
Human brain
Cullin Proteins
postnatal brain
3. Good health
Cell biology
Ubiquitin ligase
Raptor
medicine.anatomical_structure
NF-κBm
Female
Protein Binding
Proteasome Endopeptidase Complex
Repressor
General Biochemistry, Genetics and Molecular Biology
Article
03 medical and health sciences
medicine
Animals
Humans
Regulatory-Associated Protein of mTOR
TORC1
Mice, Inbred C57BL
030104 developmental biology
HEK293 Cells
proteasome
lcsh:Biology (General)
Proteasome
Proteolysis
biology.protein
CUL4B
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 22111247
- Volume :
- 29
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Cell reports
- Accession number :
- edsair.doi.dedup.....c3f335cfe1c52c4297f3cd6a8427dba6