Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C.
Oligodendrocytes secrete vesicles into the extracellular space, where they might play a role in neuron-glia communication. These exosomes are small vesicles with a diameter of 50-100 nm that are formed within multivesicular bodies and are released after fusion with the plasma membrane. The intracellular pathways that generate exosomes are poorly defined. Because Rab family guanosine triphosphatases (GTPases) together with their regulators are important membrane trafficking organizers, we investigated which Rab GTPase-activating proteins interfere with exosome release. We find that TBC1D10A-C regulate exosome secretion in a catalytic activity-dependent manner. We show that Rab35 is the target of TBC1D10A-C and that the inhibition of Rab35 function leads to intracellular accumulation of endosomal vesicles and impairs exosome secretion. Rab35 localizes to the surface of oligodendroglia in a GTP-dependent manner, where it increases the density of vesicles, suggesting a function in docking or tethering. These findings provide a basis for understanding the biogenesis and function of exosomes in the central nervous system.
Hsu
Chieh
C
Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany.
Morohashi
Yuichi
Y
Yoshimura
Shin-Ichiro
S
Manrique-Hoyos
Natalia
N
Jung
Sangyong
S
Lauterbach
Marcel A
MA
Bakhti
Mostafa
M
Grønborg
Mads
M
Möbius
Wiebke
W
Rhee
Jeongseop
J
Barr
Francis A
FA
Simons
Mikael
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology; D055354:Exosomes / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009836:Oligodendroglia / Q000166:cytology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D020690:GTPase-Activating Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C425805:TBC1D10A protein, human; C517115:TBC1D10C protein, human; C511183:RAB35 protein, human; D020691:rab GTP-Binding Proteins; D002118:Calcium
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