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

56 Pages Posted: 31 May 2019 Sneak Peek Status: Review Complete

See all articles by Stella Kouloulia

Stella Kouloulia

University of Edinburgh - Centre for Discovery Brain Sciences

Erik Ingmar-Hallin

University of Bergen - Department of Biomedicine

Konstanze Simbriger

University of Edinburgh - Centre for Discovery Brain Sciences

Ines S. Amorim

University of Edinburgh - Centre for Discovery Brain Sciences

Gilliard Lach

University of Edinburgh - Centre for Discovery Brain Sciences

Theoklitos Amvrosiadis

University of Edinburgh - Centre for Discovery Brain Sciences

Agniete Kampaite

University of Edinburgh - Centre for Discovery Brain Sciences

Seyed Mehdi Jafarnejad

Queen's University Belfast - Centre for Cancer Research and Cell Biology

Vinh Tai Truong

McGill University - Alan Edwards Centre for Research on Pain; McGill University - Department of Anesthesia

Mehdi Hooshmandi

McGill University - Alan Edwards Centre for Research on Pain; McGill University - Department of Anesthesia

Paul Skehel

University of Edinburgh - Centre for Discovery Brain Sciences

Petri Kursula

University of Bergen - Department of Biomedicine; University of Oulu - Faculty of Biochemistry and Molecular Medicine

Arkady Khoutorsky

McGill University - Alan Edwards Centre for Research on Pain; McGill University - Department of Anesthesia

Christos Gkogkas

University of Edinburgh - Centre for Discovery Brain Sciences

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Abstract

The translation initiation repressor 4E-BP2 is deamidated in 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 human brain and changes 4E-BP2 subcellular localisation, 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 AMPARs, but not NMDARs. 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.

Keywords: Asparagine deamidation, Translational control, Postnatal brain, 4E-BP2, Raptor, CUL4B, Proteasome, NF-kappa B, mTORC1

Suggested Citation

Kouloulia, Stella and Ingmar-Hallin, Erik and Simbriger, Konstanze and Amorim, Ines S. and Lach, Gilliard and Amvrosiadis, Theoklitos and Kampaite, Agniete and Jafarnejad, Seyed Mehdi and Truong, Vinh Tai and Hooshmandi, Mehdi and Skehel, Paul and Kursula, Petri and Khoutorsky, Arkady and Gkogkas, Christos, Raptor-Mediated Proteasomal Degradation of Deamidated 4E-BP2 Regulates Postnatal Neuronal Translation and NF-Kappa B Activity (May 30, 2019). CELL-REPORTS-D-19-01894. Available at SSRN: https://ssrn.com/abstract=3396492 or http://dx.doi.org/10.2139/ssrn.3396492
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Stella Kouloulia

University of Edinburgh - Centre for Discovery Brain Sciences

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

Erik Ingmar-Hallin

University of Bergen - Department of Biomedicine

Muséplassen 1
Bergen
Norway

Konstanze Simbriger

University of Edinburgh - Centre for Discovery Brain Sciences

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

Ines S. Amorim

University of Edinburgh - Centre for Discovery Brain Sciences

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

Gilliard Lach

University of Edinburgh - Centre for Discovery Brain Sciences

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

Theoklitos Amvrosiadis

University of Edinburgh - Centre for Discovery Brain Sciences

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

Agniete Kampaite

University of Edinburgh - Centre for Discovery Brain Sciences

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

Seyed Mehdi Jafarnejad

Queen's University Belfast - Centre for Cancer Research and Cell Biology

Belfast
Ireland

Vinh Tai Truong

McGill University - Alan Edwards Centre for Research on Pain

Montreal
Canada

McGill University - Department of Anesthesia

Montreal
Canada

Mehdi Hooshmandi

McGill University - Alan Edwards Centre for Research on Pain

Montreal
Canada

McGill University - Department of Anesthesia

Montreal
Canada

Paul Skehel

University of Edinburgh - Centre for Discovery Brain Sciences

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

Petri Kursula

University of Bergen - Department of Biomedicine

Muséplassen 1
Bergen
Norway

University of Oulu - Faculty of Biochemistry and Molecular Medicine

P.O. Box 3000
Oulu, 90014
Finland

Arkady Khoutorsky

McGill University - Alan Edwards Centre for Research on Pain

Montreal
Canada

McGill University - Department of Anesthesia

Montreal
Canada

Christos Gkogkas (Contact Author)

University of Edinburgh - Centre for Discovery Brain Sciences

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

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