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.


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*


  • 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