![]() Regardless of its disputable role as Rab7 GEF, Vps39 has been described as being required for the transition from early to late endosome ( Ostrowicz et al., 2010 Poteryaev et al., 2010). The identity of Rab7 GEF has been under discussion, attributing this role to either Vps39 ( Wurmser et al., 2000) or, more recently, the Mon1/Ccz1 complex ( Kinchen and Ravichandran, 2010 Nordmann et al., 2010 Poteryaev et al., 2010). The transition between early and late endosome identity has been proposed to take place via interaction of active Rab5 with Rab7 guanine nucleotide exchange factor (GEF), thus leading to the activation of Rab7. In the transition between early and late endosomes, Rab5 is replaced by Rab7 ( Rink et al., 2005), which is necessary for late endosome function ( Feng et al., 1995 Vitelli et al., 1997 Vanlandingham and Ceresa, 2009). After being endocytosed from the plasma membrane, Rab5 regulates early endosome formation and homotypic fusion ( Gorvel et al., 1991 Bucci et al., 1992 Morrison et al., 2008). Rabs regulate vesicle budding, transport, and fusion ( Zerial and McBride, 2001 Grosshans et al., 2006). The identity of endosomal compartments is ensured by specific localization of highly regulated proteins, for example Rab guanosine triphosphatases (GTPases Zerial and McBride, 2001). Molecules that are taken up from the plasma membrane are delivered to early endosomes and subsequently either travel to lysosomes via late endosomes or are returned to the plasma membrane via recycling endosomes. In eukaryotic cells endocytosis regulates the exchange of molecules both between the cell and its environment and between intracellular organelles. These results indicate that Rush controls trafficking from early to late endosomes and from late endosomes to lysosomes by modulating the activity of Rab proteins. Rush also causes formation of endosome clusters, possibly by affecting fusion of endosomes via an interaction with the class C Vps/homotypic fusion and vacuole protein-sorting (HOPS) complex. Lysosomal marker staining is decreased in Rush-overexpressing cells, pointing to a defect in the transition between late endosomes and lysosomes. Overexpression of Rush disrupts progression of endocytosed cargo and increases late endosome size. Homozygous rush mutant flies are viable but show genetic interactions with mutations in Gdi, Rab5, hrs, and carnation, the fly homologue of Vps33. Rush also directly binds to Rab GDP dissociation inhibitor (Gdi), which is involved in the activation of Rab proteins. ![]() Rush localizes to endosomes via direct binding of its FYVE (Fab1p, YOTB, Vac1p, EEA1) domain to phosphatidylinositol 3-phosphate. We have identified the highly conserved protein Rush hour (Rush) and show that it participates in the regulation of endocytosis. Endocytosis regulates multiple cellular processes, including the protein composition of the plasma membrane, intercellular signaling, and cell polarity.
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