The GTPase Rab35 regulates the release of small vesicles called exosomes from the surface of glial cells, say Hsu et al.
Exosomes are formed in the lumen of specialized endosomes called multivesicular bodies (MVBs), which fuse with the plasma membrane to secrete the vesicles extracellularly. The process was first described as a way for differentiating reticulocytes to quickly discard their unwanted cellular contents. In other cell types, exosomes have signaling functions or mediate the transfer of mRNAs between cells. Oligodendrocytes secrete a lot of exosomes, but their role in the central nervous system isn't clear—partly because molecules controlling the vesicles' release haven't been identified.
Because Rabs and their accessory proteins regulate membrane trafficking, Hsu et al. investigated their function in exosome secretion by screening all 38 Rab GTPase-activating proteins (GAPs). Five GAPs inhibited exosome release from oligodendrocytes, including three closely related proteins that all switched Rab35 to the inactive, GDP-bound state. Knocking down Rab35 or expressing a dominant-negative version of the GTPase also blocked exosome secretion. Rab35 prepared MVBs for exocytosis by docking them to the plasma membrane.
Both Rab35 and MVBs were found in the myelin compartment of oligodendrocytes, which enwraps and insulates nerve cell axons. This suggests that exosomes released from glial cells could communicate with neighboring neurons. Senior author Mikael Simons is also interested in a possible connection to multiple sclerosis (MS): an abundant component of glial cell exosomes is a myelin protein called PLP—a common autoantigen in MS patients.