The integrated stress response effector GADD34 is repurposed by neurons to promote stimulus-induced translation

Neuronal protein synthesis is required for long-lasting plasticity and long-term memory consolidation. Dephosphorylation of eukaryotic initiation factor 2α is one of the key translational control events that is required to increase de novo protein synthesis that underlies long-lasting plasticity and memory consolidation. Here, we interrogate the molecular pathways of translational control that are triggered by neuronal stimulation with brain-derived neurotrophic factor (BDNF), which results in eukaryotic initiation factor 2α (eIF2α) dephosphorylation and increases in de novo protein synthesis. Primary rodent neurons exposed to BDNF display elevated translation of GADD34, which facilitates eIF2α dephosphorylation and subsequent de novo protein synthesis. Furthermore, GADD34 requires G-actin generated by cofilin to dephosphorylate eIF2α and enhance protein synthesis. Finally, GADD34 is required for BDNF-induced translation of synaptic plasticity-related proteins. Overall, we provide evidence that neurons repurpose GADD34, an effector of the integrated stress response, as an orchestrator of rapid increases in eIF2-dependent translation in response to plasticity-inducing stimuli. [Display omitted] •GADD34 is translated by neurons in response to neuronal activation•GADD34 promotes fast dephosphorylation of eIF2α and elevation of neuronal protein synthesis•GADD34-eIF2α interaction requires actin monomers and cofilin activity•Artificially increasing cofilin activity in neurons promotes de novo protein synthesis Oliveira et al. demonstrate that sharp increases in protein synthesis resulting from neuronal activation require GADD34-induced eIF2α dephosphorylation. GADD34 expression is tied to the regulation of mRNA translation. Neuronal GADD34 then recruits actin monomers to stabilize its interaction with eIF2α and promote its dephosphorylation.