eIF4E phosphorylation recruits β-catenin to mRNA cap and promotes Wnt pathway translation in dentate gyrus LTP maintenance

Sudarshan Patil; Kleanthi Chalkiadaki; Tadiwos F Mergiya; Konstanze Krimbacher; Inês S Amorim; Shreeram Akerkar; Christos G Gkogkas; Clive R Bramham

doi:10.1016/j.isci.2023.106649

eIF4E phosphorylation recruits β-catenin to mRNA cap and promotes Wnt pathway translation in dentate gyrus LTP maintenance

iScience. 2023 Apr 15;26(5):106649. doi: 10.1016/j.isci.2023.106649. eCollection 2023 May 19.

Authors

Sudarshan Patil¹, Kleanthi Chalkiadaki², Tadiwos F Mergiya^{1

3}, Konstanze Krimbacher⁴, Inês S Amorim⁴, Shreeram Akerkar¹, Christos G Gkogkas², Clive R Bramham^{1

3}

Affiliations

¹ Department of Biomedicine Jonas Lies vei 91, University of Bergen, 5009 Bergen, Norway.
² Biomedical Research Institute, Foundation for Research and Technology-Hellas, 45110 Ioannina, Greece.
³ Mohn Research Center for the Brain, University of Bergen, Bergen, Norway.
⁴ Center for Discovery Brain Sciences, University of Edinburgh, EH8 9XD Edinburgh, UK.

Abstract

The mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E), is crucial for translation and regulated by Ser209 phosphorylation. However, the biochemical and physiological role of eIF4E phosphorylation in translational control of long-term synaptic plasticity is unknown. We demonstrate that phospho-ablated Eif4e^S209A Knockin mice are profoundly impaired in dentate gyrus LTP maintenance in vivo, whereas basal perforant path-evoked transmission and LTP induction are intact. mRNA cap-pulldown assays show that phosphorylation is required for synaptic activity-induced removal of translational repressors from eIF4E, allowing initiation complex formation. Using ribosome profiling, we identified selective, phospho-eIF4E-dependent translation of the Wnt signaling pathway in LTP. Surprisingly, the canonical Wnt effector, β-catenin, was massively recruited to the eIF4E cap complex following LTP induction in wild-type, but not Eif4e^S209A, mice. These results demonstrate a critical role for activity-evoked eIF4E phosphorylation in dentate gyrus LTP maintenance, remodeling of the mRNA cap-binding complex, and specific translation of the Wnt pathway.

Keywords: Cell biology; Molecular biology.