Exchange of information through extracellular vesicles, including exosomes, has emerged to be an important tool of intercellular communication necessary for the physiology of neural systems. Exosomes also have a sinister role in the propagation of toxic amyloid proteins in neurodegenerative conditions, including Alzheimer’s and Parkinson’s diseases. However, mechanisms underlying biogenesis of exosomes and the cargo sorting remain unclear. We present here the mechanism of regulation of exosome biogenesis by sphingosine 1-phosphate (S1P) signaling. During late endosome maturation, cargo molecules are sorted into intralumenal vesicles (ILVs) of multivesicular endosomes (MVEs), and are either delivered to lysosomesfor degradation or fused with the plasma membranes for exosome release. We have recently found that inhibitory G protein (Gi)-coupled 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. These findings shed light on the understanding as to how cargo molecules are sorted into exosomal ILVs and provide an important clue to the development of molecule-based treatment of exosome-mediated intractable diseases including neurodegenerative disorders. Kajimoto T, Okada T, Miya S, Zhang L, Nakamura S (2013) Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes. Nat Commun 4: 2712. doi: 10.1038
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