Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes

Nat Commun. 2013;4:2712. doi: 10.1038/ncomms3712.


During late endosome maturation, cargo molecules are sorted into intralumenal vesicles (ILVs) of multivesicular endosomes (MVEs), and are either delivered to lysosomes for degradation or fused with the plasma membranes for exosome release. The mechanism underlying formation of exosomal ILVs and cargo sorting into ILVs destined for exosome release is still unclear. Here we show that inhibitory G protein (Gi)-coupled sphingosine 1-phosphate (S1P) receptors regulate exosomal MVE maturation. Gi-coupled S1P receptors on MVEs are constitutively activated through a constant supply of S1P via autocrine activation within organelles. We also found that the continuous activation of Gi-coupled S1P receptors on MVEs is essential for cargo sorting into ILVs destined for exosome release. Our results reveal a mechanism underlying ESCRT-independent maturation of exosomal MVEs.

MeSH terms

  • Adsorption
  • Bacterial Proteins / metabolism
  • Cell Membrane / metabolism
  • Endosomes / metabolism*
  • Exosomes / metabolism*
  • Fluorescence Recovery After Photobleaching
  • Fluorescence Resonance Energy Transfer
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Luminescent Proteins / metabolism
  • Lysophospholipids / metabolism
  • Lysosomes / metabolism
  • Protein Transport
  • RNA, Small Interfering / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Lysosphingolipid / metabolism*
  • Signal Transduction
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Tetraspanin 30 / metabolism


  • Bacterial Proteins
  • Cyan Fluorescent Protein
  • Luminescent Proteins
  • Lysophospholipids
  • RNA, Small Interfering
  • Receptors, G-Protein-Coupled
  • Receptors, Lysosphingolipid
  • Tetraspanin 30
  • yellow fluorescent protein, Bacteria
  • Green Fluorescent Proteins
  • sphingosine 1-phosphate
  • Sphingosine