Activation of a GPCR leads to eIF4G phosphorylation at the 5′ cap and to IRES-dependent translation

Abstract

The control of mRNA translation has been mainly explored in response to activated tyrosine kinase receptors. In contrast, mechanistic details on the translational machinery are far less available in the case of ligand-bound G protein-coupled receptors (GPCRs). In this study, using the FSH receptor (FSH-R) as a model receptor, we demonstrate that part of the translational regulations occurs by phosphorylation of the translation pre-initiation complex scaffold protein, eukaryotic initiation factor 4G (eIF4G), in HEK293 cells stably expressing the FSH-R. This phosphorylation event occurred when eIF4G was bound to the mRNA 5 0 cap, and probably involves mammalian target of rapamycin. This regulation might contribute to cap-dependent translation in response to FSH. The cap-binding protein eIF4E also had its phosphorylation level enhanced upon FSH stimulation. We also show that FSH-induced signaling not only led to cap-dependent translation but also to internal ribosome entry site (IRES)-dependent translation of some mRNA. These data add detailed information on the molecular bases underlying the regulation of selective mRNA translation by a GPCR, and a topological model recapitulating these mechanisms is proposed.

FSH for the Treatment of Male Infertility

“…As for the p70S6K pathway, the role of β-arrestins in its activation in seminiferous tubules or in follicles has not been clarified yet, although in Sertoli cells, β-arrestin 1 and p70S6K can be identified in common protein complexes [27]. p70S6K activation relies on protein kinase B (Akt) [28,32], and activation of this pathway is presumably responsible for enhancing mRNA translation measured in response to FSH [33,34], as a hallmark of FSH anabolic function and trophic role. Interestingly, FSH-activated Akt appears to protect cells from autophagy, by inhibiting the transcription factor forkhead box protein O1 (FOXO1) and promoting its nuclear exclusion.…”

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

“…The phosphorylation of these proteins increases the efficiency with which the cap-dependent translation complex (consisting of eIF4F, eIF4B, and PABP) assembles and functions. Phosphorylation of eIF4G, the scaffold of the cap-binding complex, increases both cap- and IRES-dependent translation (León et al, 2014). eIF4B, which enhances the activity of the helicase eIF4A, requires phosphorylation to associate with eIF4A (Andreou et al, 2017; Holz et al, 2005).…”

Towards the convergent therapeutic potential of GPCRs in autism spectrum disorders

“…Following activation, GPCRs are internalized in intracellular compartments (e.g., endosomes) together with their transducers and participate in the signalling cascades (Vilardaga et al, 2022). Downstream intracellular signalling network leads to integrated cellular processes, translation of specific mRNAs (Musnier et al, 2012;León et al, 2014;Tréfier et al, 2018) and gene transcription via the transcription factor cAMPresponsive element binding protein (CREB), among many others. Globally, GPCRs are key master upstream regulators of Wnt/β-catenin, ERK, PKC, Pi3K/Akt, CREB, PTEN and mTOR intracellular pathways that are convergently dysregulated in ASD (O'Roak et al, 2012;Gazestani et al, 2019;Pintacuda et al, 2023).…”