title: Chemotactic G protein-coupled receptors control cell migration by repressing autophagosome biogenesis.
abstract: Chemotactic migration is a fundamental behavior of cells and its regulation is particularly relevant in physiological processes such as organogenesis and angiogenesis, as well as in pathological processes such as tumor metastasis. The majority of chemotactic stimuli activate cell surface receptors that belong to the G protein-coupled receptor (GPCR) superfamily. Although the autophagy machinery has been shown to play a role in cell migration, its mode of regulation by chemotactic GPCRs remains largely unexplored. We found that ligand-induced activation of 2 chemotactic GPCRs, the chemokine receptor CXCR4 and the urotensin 2 receptor UTS2R, triggers a marked reduction in the biogenesis of autophagosomes, in both HEK-293 and U87 glioblastoma cells. Chemotactic GPCRs exert their anti-autophagic effects through the activation of CAPNs, which prevent the formation of pre-autophagosomal vesicles from the plasma membrane. We further demonstrated that CXCR4- or UTS2R-induced inhibition of autophagy favors the formation of adhesion complexes to the extracellular matrix and is required for chemotactic migration. Altogether, our data reveal a new link between GPCR signaling and the autophagy machinery, and may help to envisage therapeutic strategies in pathological processes such as cancer cell invasion.
authors.affiliation: a Normandie Univ, UNIROUEN, INSERM, DC2N , Rouen , France.|b Institute for Research and Innovation in Biomedicine (IRIB) , Rouen , France.
authors.forename: Pierre-Michaël
authors.initials: PM
authors.lastname: Coly
authors.affiliation: a Normandie Univ, UNIROUEN, INSERM, DC2N , Rouen , France.|b Institute for Research and Innovation in Biomedicine (IRIB) , Rouen , France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Perzo
authors.affiliation: a Normandie Univ, UNIROUEN, INSERM, DC2N , Rouen , France.|b Institute for Research and Innovation in Biomedicine (IRIB) , Rouen , France.
authors.forename: Vadim
authors.initials: V
authors.lastname: Le Joncour
authors.affiliation: a Normandie Univ, UNIROUEN, INSERM, DC2N , Rouen , France.|b Institute for Research and Innovation in Biomedicine (IRIB) , Rouen , France.
authors.forename: Céline
authors.initials: C
authors.lastname: Lecointre
authors.affiliation: a Normandie Univ, UNIROUEN, INSERM, DC2N , Rouen , France.|b Institute for Research and Innovation in Biomedicine (IRIB) , Rouen , France.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Schouft
authors.affiliation: a Normandie Univ, UNIROUEN, INSERM, DC2N , Rouen , France.|b Institute for Research and Innovation in Biomedicine (IRIB) , Rouen , France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Desrues
authors.affiliation: a Normandie Univ, UNIROUEN, INSERM, DC2N , Rouen , France.|b Institute for Research and Innovation in Biomedicine (IRIB) , Rouen , France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Tonon
authors.affiliation: a Normandie Univ, UNIROUEN, INSERM, DC2N , Rouen , France.|b Institute for Research and Innovation in Biomedicine (IRIB) , Rouen , France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Wurtz
authors.affiliation: a Normandie Univ, UNIROUEN, INSERM, DC2N , Rouen , France.|b Institute for Research and Innovation in Biomedicine (IRIB) , Rouen , France.
authors.forename: Pierrick
authors.initials: P
authors.lastname: Gandolfo
authors.affiliation: a Normandie Univ, UNIROUEN, INSERM, DC2N , Rouen , France.|b Institute for Research and Innovation in Biomedicine (IRIB) , Rouen , France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Castel
authors.affiliation: a Normandie Univ, UNIROUEN, INSERM, DC2N , Rouen , France.|b Institute for Research and Innovation in Biomedicine (IRIB) , Rouen , France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Morin
mesh_terms: D000071182:Autophagosomes / Q000378:metabolism*; D001343:Autophagy; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism; D000071183:Autophagy-Related Proteins / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D002154:Calpain / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002633:Chemotaxis; D004705:Endocytosis; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D002154:Calpain; D019869:Phosphatidylinositol 3-Kinases; D019718:Receptors, CXCR4; D043562:Receptors, G-Protein-Coupled; D058570:TOR Serine-Threonine Kinases; C518959:ATG16L1 protein, human; C527276:CXCR4 protein, human; C121697:UTS2R protein, human
keywords: CXCR4; GPCR; autophagosome biogenesis; cell adhesion; chemotactic migration; urotensin II