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

Léon-Huaman, Kelly; Boulo, Thomas; Musnier, Astrid; Morales, Julia; Gauthier, Christophe; Dupuy, Laurence; Heyne, Steffen; Backofen, Rolf; Poupon, Anne; Cormier, Patrick; Reiter, Eric; Crepieux, Pascale

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

2014

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. Here, using the follicle-stimulating hormone receptor 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, in HEK293 cells stably expressing the follicle-stimulating hormone receptor. This phosphorylation event occurred when eukaryotic initiation factor 4G was bound to the mRNA 5'cap, and likely involves mammalian target of rapamycin. This regulation might contribute to cap-dependent translation in response to follicle-stimulating hormone. The cap-binding protein eukaryotic initiation factor 4E also had its phosphorylation level enhanced upon follicle-stimulating hormone stimulation. In addition, we also show that follicle-stimulating hormone-induced signaling not only led to cap-dependent translation but also to internal ribosome entry site-dependent translation of some mRNA. These data add detailed information on the molecular bases underlying the regulation of selective mRNA translation by a G protein-coupled receptor, and a topological model recapitulating these mechanisms is proposed.

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