GPR50-Ctail cleavage and nuclear translocation: a new signal transduction mode for G protein-coupled receptors
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
GPR50‑Ctail cleavage and nuclear translocation: a new signal transduction mode for G protein‑coupled receptors Raise Ahmad1 · Olivier Lahuna1 · Anissa Sidibe1 · Avais Daulat1 · Qiang Zhang1 · Marine Luka1 · Jean‑Luc Guillaume1 · Sarah Gallet2 · François Guillonneau1 · Juliette Hamroune1 · Sophie Polo3 · Vincent Prévot2 · Philippe Delagrange4 · Julie Dam1 · Ralf Jockers1 Received: 14 July 2019 / Revised: 21 November 2019 / Accepted: 23 December 2019 © Springer Nature Switzerland AG 2020
Abstract Transmission of extracellular signals by G protein-coupled receptors typically relies on a cascade of intracellular events initiated by the activation of heterotrimeric G proteins or β-arrestins followed by effector activation/inhibition. Here, we report an alternative signal transduction mode used by the orphan GPR50 that relies on the nuclear translocation of its carboxylterminal domain (CTD). Activation of the calcium-dependent calpain protease cleaves off the CTD from the transmembranebound GPR50 core domain between Phe-408 and Ser-409 as determined by MALDI-TOF-mass spectrometry. The cytosolic CTD then translocates into the nucleus assisted by its ‘DPD’ motif, where it interacts with the general transcription factor TFII-I to regulate c-fos gene transcription. RNA-Seq analysis indicates a broad role of the CTD in modulating gene transcription with ~ 8000 differentially expressed genes. Our study describes a non-canonical, direct signaling mode of GPCRs to the nucleus with similarities to other receptor families such as the NOTCH receptor Keywords GPCR · Orphan · Calpain · GPR50 · Proteolytic cleavage · Signal transduction
Introduction G protein-coupled receptors (GPCRs) constitute the largest membrane receptor family in humans. They respond to a wide variety of extracellular molecules and play a crucial role in cell-to-cell communication by transmitting extracellular signals into cells. The current paradigm of intracellular signal transduction by GPCRs relies on a Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-019-03440-7) contains supplementary material, which is available to authorized users. * Ralf Jockers [email protected] 1
Université de Paris, Institut Cochin, CNRS, INSERM, 22 rue Méchain, 75014 Paris, France
2
Jean-Pierre Aubert Research Center, U837 Lille, France
3
Epigenetics and Cell Fate Centre, UMR7216, CNRS, Paris Diderot University, Paris, France
4
Pôle D’Innovation Thérapeutique Neuropsychiatrie, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy, France
multistep pathway initiated by the engagement of heterotrimeric G proteins or β-arrestins, followed by the generation of soluble second messengers and activation/inhibition of various effectors [1]. Among the approximately 400 non-odorant GPCRs in humans, more than 100 are orphans for which no endogenous ligand has been identified yet. GPR50 is one of these orphans. In the absence of any known ligand f
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