title: Syntenin-ALIX exosome biogenesis and budding into multivesicular bodies are controlled by ARF6 and PLD2.
abstract: Exosomes are small vesicles that are secreted by cells and act as mediators of cell to cell communication. Because of their potential therapeutic significance, important efforts are being made towards characterizing exosomal contents. However, little is known about the mechanisms that govern exosome biogenesis. We have recently shown that the exosomal protein syntenin supports exosome production. Here we identify the small GTPase ADP ribosylation factor 6 (ARF6) and its effector phospholipase D2 (PLD2) as regulators of syntenin exosomes. ARF6 and PLD2 affect exosomes by controlling the budding of intraluminal vesicles (ILVs) into multivesicular bodies (MVBs). ARF6 also controls epidermal growth factor receptor degradation, suggesting a role in degradative MVBs. Yet ARF6 does not affect HIV-1 budding, excluding general effects on Endosomal Sorting Complexes Required for Transport. Our study highlights a novel pathway controlling ILV budding and exosome biogenesis and identifies an unexpected role for ARF6 in late endosomal trafficking.
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France.
authors.forename: Rania
authors.initials: R
authors.lastname: Ghossoub
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Lembo
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Rubio
authors.affiliation: 1] Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France [2] Department of Human Genetics, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Carole Baron
authors.initials: CB
authors.lastname: Gaillard
authors.affiliation: 1] Institut Pasteur, Department of Immunology, Lymphocyte Cell Biology Unit, 75015 Paris, France [2] CNRS, URA-1961, 75015 Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bouchet
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, UPR-3212, Centre National de la Recherche Scientifique, and Université de Strasbourg, 67084 Strasbourg, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vitale
authors.affiliation: Veterinary Research Institute, Hudcova 70, CZ-621 00 Brno, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Slavík
authors.affiliation: Veterinary Research Institute, Hudcova 70, CZ-621 00 Brno, Czech Republic.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Machala
authors.affiliation: 1] Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France [2] Department of Human Genetics, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Pascale
authors.initials: P
authors.lastname: Zimmermann
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D055354:Exosomes / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D057146:Multivesicular Bodies / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D053676:Syntenins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000089982:ADP-Ribosylation Factor 6; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C117020:PDCD6IP protein, human; D053676:Syntenins; D066246:ErbB Receptors; C105606:phospholipase D2; D010739:Phospholipase D; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human