1. Raptor-mediated proteasomal degradation of deamidated 4E-BP2 regulates postnatal neuronal translation and NF-κB activity
- Author
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Kouloulia, S. (Stella), Hallin, E. I. (Erik I.), Simbriger, K. (Konstanze), Amorim, I. S. (Inês S.), Lach, G. (Gilliard), Amvrosiadis, T. (Theoklitos), Chalkiadaki, K. (Kleanthi), Kampaite, A. (Agniete), Truong, V. T. (Vinh Tai), Hooshmandi, M. (Mehdi), Jafarnejad, S. M. (Seyed Mehdi), Skehel, P. (Paul), Kursula, P. (Petri), Khoutorsky, A. (Arkady), Gkogkas, C. G. (Christos G.), Kouloulia, S. (Stella), Hallin, E. I. (Erik I.), Simbriger, K. (Konstanze), Amorim, I. S. (Inês S.), Lach, G. (Gilliard), Amvrosiadis, T. (Theoklitos), Chalkiadaki, K. (Kleanthi), Kampaite, A. (Agniete), Truong, V. T. (Vinh Tai), Hooshmandi, M. (Mehdi), Jafarnejad, S. M. (Seyed Mehdi), Skehel, P. (Paul), Kursula, P. (Petri), Khoutorsky, A. (Arkady), and Gkogkas, C. G. (Christos G.)
- 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.
- Published
- 2019