Rab35 drives exosome secretion

Rab35 drives exosome secretion T he GTPase Rab35 regulates the release of small vesi-cles 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 fi rst 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 identifi ed. Because Rabs and their accessory proteins regulate membrane traffi cking, Hsu et al. investigated their function in exosome secretion by screening all 38 Rab GTPase-activating proteins (GAPs). Five GAPs inhibited exosome release from oligoden-drocytes, 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. C ortical localiza-tion of the small GTPase Rho1 activates the JNK sig-naling pathway to kill Drosophila epithelial cells, Neisch et al. reveal. Cell death by apopto-sis is elevated in flies missing the epithelial protein moesin, which organizes the apical cortex of cells, partly by linking the plasma membrane to the underlying actin cytoskeleton. Moesin also regulates Rho1, but the GTPase's contribution to apoptosis was unclear. Neisch et al. saw that plasma membrane levels of Rho1 were increased in fl y epithelia lacking moesin, and that removing one copy of the GTPase rescued the cells from apoptosis. In addition, overexpressing Rho1 boosted cell death by up-regulating the pro-apoptotic gene hid. The authors then investigated the JNK signaling pathway, which can promote apoptosis in Drosophila imaginal disc epithelia. The pathway was activated in the absence of moesin, and inhibiting different steps of the signaling cascade blocked Rho1-induced death. Rho1 activated JNK …