Syntenin-ALIX exosome biogenesis and budding into multivesicular bodies are controlled by ARF6 and PLD2

Rania Ghossoub; Frédérique Lembo; Aude Rubio; Carole Baron Gaillard; Jérôme Bouchet; Nicolas Vitale; Josef Slavík; Miroslav Machala; Pascale Zimmermann

doi:10.1038/ncomms4477

Syntenin-ALIX exosome biogenesis and budding into multivesicular bodies are controlled by ARF6 and PLD2

Nat Commun. 2014 Mar 18:5:3477. doi: 10.1038/ncomms4477.

Authors

Rania Ghossoub¹, Frédérique Lembo¹, Aude Rubio¹, Carole Baron Gaillard², Jérôme Bouchet³, Nicolas Vitale⁴, Josef Slavík⁵, Miroslav Machala⁵, Pascale Zimmermann²

Affiliations

¹ Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France.
² 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.
³ 1] Institut Pasteur, Department of Immunology, Lymphocyte Cell Biology Unit, 75015 Paris, France [2] CNRS, URA-1961, 75015 Paris, France.
⁴ Institut des Neurosciences Cellulaires et Intégratives, UPR-3212, Centre National de la Recherche Scientifique, and Université de Strasbourg, 67084 Strasbourg, France.
⁵ Veterinary Research Institute, Hudcova 70, CZ-621 00 Brno, Czech Republic.

PMID: 24637612
DOI: 10.1038/ncomms4477

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.

MeSH terms

ADP-Ribosylation Factor 6
ADP-Ribosylation Factors / genetics
ADP-Ribosylation Factors / metabolism*
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / metabolism*
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Cell Line
Endosomal Sorting Complexes Required for Transport / genetics
Endosomal Sorting Complexes Required for Transport / metabolism*
ErbB Receptors / metabolism
Exosomes / enzymology
Exosomes / genetics
Exosomes / metabolism*
HIV Infections / genetics
HIV Infections / metabolism
HIV Infections / virology
HIV-1 / physiology
Humans
Multivesicular Bodies / enzymology
Multivesicular Bodies / genetics
Multivesicular Bodies / metabolism*
Phospholipase D / genetics
Phospholipase D / metabolism*
Protein Transport
Syntenins / genetics
Syntenins / metabolism*

Substances

ADP-Ribosylation Factor 6
Calcium-Binding Proteins
Cell Cycle Proteins
Endosomal Sorting Complexes Required for Transport
PDCD6IP protein, human
Syntenins
ErbB Receptors
phospholipase D2
Phospholipase D
ADP-Ribosylation Factors
ARF6 protein, human