Follicle-Stimulating Hormone Receptor: Advances and Remaining Challenges

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Méthodes d’étude du traductome régulé par les récepteurs couplés aux protéines G

National audienceWith the advent of next-generation sequencing technologies, identifying the translatome, which includes genome-wide ribosome-associated mRNAs, provides new opportunities to define faithfully the protein repertoire of a cell, as opposed to transcriptomic approaches. In addition, the role that extracellular signals such as hormonal modulations could play on the translatome remains to be deciphered. In particular, the regulation of the translatome by G protein-coupled receptors (GPCR) is still poorly described, albeit the trophic role that many receptors of this family play in their target cells. Here, we provide an overview of the current methods that are used to study the translatome, applied to the GPCR receptor family.Depuis l’avènement des méthodes de séquençage à haut débit, l’identification du traductome, qui comprend l’ensemble des ARNm associés aux ribosomes, ouvre de nouvelles perspectives pour définir le répertoire des protéines réellement exprimées dans une cellule, contrairement au séquençage du transcriptome correspondant. De plus, l’impact que les signaux extracellulaires tels que des modulations hormonales peuvent avoir sur le traductome reste méconnu. En particulier, la régulation du traductome par les récepteurs couplés aux protéines G (RCPG) est un domaine encore peu exploré, alors que de nombreux récepteurs de cette famille jouent un rôle trophique très important dans leur cellule cible. L’objectif de cette revue est de présenter les méthodes les plus utilisées pour étudier le traductome, en les appliquant aux RCPG

G Protein-Coupled Receptors As Regulators of Localized Translation: The Forgotten Pathway?

International audienceG protein-coupled receptors (GPCRs) exert their physiological function by transducing a complex signaling network that coordinates gene expression and dictates the phenotype of highly differentiated cells. Much is known about the gene networks they transcriptionally regulate upon ligand exposure in a process that takes hours before a new protein is synthesized. However, far less is known about GPCR impact on the translational machinery and subsequent mRNA translation, although this gene regulation level alters the cell phenotype in a strikingly different timescale. In fact, mRNA translation is an early response kinetically connected to signaling events, hence it leads to the synthesis of a new protein within minutes following receptor activation. By these means, mRNA translation is responsive to subtle variations of the extracellular environment. In addition, when restricted to cell subcellular compartments, local mRNA translation contributes to cell micro-specialization, as observed in synaptic plasticity or in cell migration. The mechanisms that control where in the cell an mRNA is translated are starting to be deciphered. But how an extracellular signal triggers such local translation still deserves extensive investigations. With the advent of high-throughput data acquisition, it now becomes possible to review the current knowledge on the translatome that some GPCRs regulate, and how this information can be used to explore GPCR-controlled local translation of mRNAs

Regulation of the translatome by a GPCR, the follicle-stimulating hormone receptor, in primary ra Sertoli cells

National audienc

The translatome of the FSH receptor reveals tha several FSH-responsive signaling effectors are co-translated in primary rat Sertoli cells

The translatome of the FSH receptor reveals tha several FSH-responsive signaling effectors are co-translated in primary rat Sertoli cells. 2. Journées du GdR 3606 Repr

Proteoliposomes as new tool to select active VHH binders by phage display technology

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β-arrestin signalling and bias in hormone-responsive GPCRs

International audienceG protein-coupled receptors (GPCRs) play crucial roles in the ability of target organs to respond to hormonal cues. GPCRs’ activation mechanisms have long been considered as a two-state process connecting the agonist-bound receptor to heterotrimeric G proteins. This view is now challenged as mounting evidence point to GPCRs being connected to large arrays of transduction mechanisms involving heterotrimeric G proteins as well as other players. Amongst the G protein-independent transduction mechanisms, those elicited by β-arrestins upon their recruitment to the active receptors are by far the best characterized and apply to most GPCRs. These concepts, in conjunction with remarkable advances made in the field of GPCR structural biology and biophysics, have supported the notion of ligand-selective signalling also known as pharmacological bias. Interestingly, recent reports have opened intriguing prospects to the way β-arrestins control GPCR-mediated signalling in space and time within the cells. In the present paper, we review the existing evidence linking endocrine-related GPCRs to β-arrestin recruitement, signalling, pathophysiological implications and selective activation by biased ligands and/or receptor modifications. Emerging concepts surrounding β-arrestin-mediated transduction are discussed in the light of the peculiarities of endocrine systems

G protein-dependent signaling triggers a β-arrestin-scaffolded p70S6K/ rpS6 module that controls 5'TOP mRNA translation

International audienceMany interaction partners of β-arrestins intervene in the control of mRNA translation. However, how β-arrestins regulate this cellular process has been poorly explored. In this study, we show that β-arrestins constitutively assemble a p70S6K/ribosomal protein S6 (rpS6) complex in HEK293 cells and in primary Sertoli cells of the testis. We demonstrate that this interaction is direct, and experimentally validate the interaction interface between β-arrestin 1 and p70S6K predicted by our docking algorithm. Like most GPCRs, the biological function of follicle-stimulating hormone receptor (FSHR) is transduced by G proteins and β-arrestins. Upon follicle-stimulating hormone (FSH) stimulation, activation of G protein–dependent signaling enhances p70S6K activity within the β-arrestin/p70S6K/rpS6 preassembled complex, which is not recruited to the FSHR. In agreement, FSH-induced rpS6 phosphorylation within the β-arrestin scaffold was decreased in cells depleted of Gαs. Integration of the cooperative action of β-arrestin and G proteins led to the translation of 5′ oligopyrimidine track mRNA with high efficacy within minutes of FSH input. Hence, this work highlights new relationships between G proteins and β-arrestins when acting cooperatively on a common signaling pathway, contrasting with their previously shown parallel action on the ERK MAP kinase pathway. In addition, this study provides insights into how GPCR can exert trophic effects in the cell

G protein-dependent signaling triggers a β-arrestin-scaffolded p70S6K/ rpS6 module that controls 5'TOP mRNA translation in FSH stimulated cells

International audienc