eIF4B phosphorylation at Ser504 links synaptic activity with protein translation in physiology and pathology

Abstract

Neuronal physiology requires activity-driven protein translation, a process in which translation initiation factors are key players. We focus on eukaryotic initiation factor 4B (eIF4B), a regulator of protein translation, whose function in neurons is undetermined. We show that neuronal activity affects eIF4B phosphorylation and identify Ser504 as a phosphorylation site regulated by casein kinases and sensitive to the activation of metabotropic glutamate receptors. Ser504 phosphorylation increases eIF4B recruitment to the pre-initiation complex and influences eIF4B localization at synapses. Moreover, Ser504 phosphorylation modulates the translation of protein kinase Mζ. Therefore, by sensing synaptic activity, eIF4B could adjust translation to neuronal needs, promoting adaptive changes in synaptic plasticity. We also show that Ser504 phosphorylation is increased in vivo in a rat model of epilepsy during epileptogenesis i.e. when translation drives maladaptive synaptic changes. We propose eIF4B as a mediator between neuronal activity and translation, with relevance in the control of synaptic plasticity.

eIF4B and eIF4H mediate GR production from expanded G4C2 in a Drosophila model for C9orf72-associated ALS

“…However, no significant changes were observed for phospho-eIF4B at Ser422, an inhibitory modification [69, 77], in four C9+ derived cell lines versus five control cell lines. Extended analyses are needed to increase the sample size and to test for eIF4B phosphorylation at other marks [9, 89]. Overall, we hypothesize that eIF4H is downregulated as the result of compensatory mechanisms: cells may actively downregulate eIF4H to reduce expression of toxic GR dipeptide.…”

“…Interestingly, yeast and flies (see Fig. 3b) with downregulated eIF4B or eIF4H are viable [2, 15, 33] and eIF4H +/− mice do not have notable deficits [11]; although eIF4B and eIF4H have been suggested to be important for brain development [9, 11, 20, 67]. The downstream consequences of eIF4H downregulation in C9+ ALS/FTD may be broader than simply altering RAN-translation as depletion of eIF4B and eIF4H in cultured cells has been shown to induce stress granule formation [54].…”

Neonatal maternal deprivation impairs localized de novo activity-induced protein translation at the synapse in the rat hippocampus

“…Akt signaling is critical for activity-dependent dendritic translation [ 26 , 27 , 31–33 ]. Neuronal activity robustly stimulates local Akt phosphorylation and signaling, which allows the initiation of synaptic protein translation [ 28 , 62 ]. In the present study, we observed that the loss of activity-dependent translation induced by neonatal maternal separation was accompanied by diminished expression of active phosphorylated Akt (at pThr308 and PSer473 Akt) in synaptoneurosomes.…”

Serine-threonine protein phosphatases: Lost in translation

“…Insulin-induced eIF4B phosphorylation correlates with an observed increase in translation [33], while heat shock and serum starvation cause its dephosphorylation. Identified phosphorylation sites include Ser422 (phosphorylated by S6K and p90 ribosomal protein S6 kinase (RSK) [34] or by PKB [35]), Ser406 (depends on MEK and mTOR activity [35]), Ser496 (by Pim1 and Pim2 kinases [36]), and Ser504 (by casein kinase [37]). Phosphorylation of these residues was demonstrated to modulate eIF4B translational activity.…”