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.

] Centre de Recherche en Cancérologie de Marseille Inserm U1068 CNRS UMR7258 Aix Marseille Université Institut Paoli Calmettes 13009 Marseille France [2] Department of Human Genetics KU Leuven B 3000 Leuven Belgium

] Institut Pasteur Department of Immunology Lymphocyte Cell Biology Unit 75015 Paris France [2] CNRS URA 1961 75015 Paris France

Centre de Recherche en Cancérologie de Marseille Inserm U1068 CNRS UMR7258 Aix Marseille Université Institut Paoli Calmettes 13009 Marseille France

Institut des Neurosciences Cellulaires et Intégratives UPR 3212 Centre National de la Recherche Scientifique and Université de Strasbourg 67084 Strasbourg France

Veterinary Research Institute Hudcova 70 CZ 621 00 Brno Czech Republic

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