The Rab5 effector Rabankyrin-5 regulates and coordinates different endocytic mechanisms |
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| Authors: | Schnatwinkel Carsten Christoforidis Savvas Lindsay Margaret R Uttenweiler-Joseph Sandrine Wilm Matthias Parton Robert G Zerial Marino |
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| Affiliation: | 1 Max-Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany, 2 Laboratory of Biological Chemistry, Medical School, University of Ioannina, Ioannina, Greece, 3 Institute for Molecular Bioscience, Centre for Microscopy and Microanalysis, School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia, 4 European Molecular Biology Laboratory, Heidelberg, Germany |
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| Abstract: | The small GTPase Rab5 is a key regulator of clathrin-mediated endocytosis. On early endosomes, within a spatially restricted domain enriched in phosphatydilinositol-3-phosphate [PI(3)P], Rab5 coordinates a complex network of effectors that functionally cooperate in membrane tethering, fusion, and organelle motility. Here we discovered a novel PI(3)P-binding Rab5 effector, Rabankyrin-5, which localises to early endosomes and stimulates their fusion activity. In addition to early endosomes, however, Rabankyrin-5 localises to large vacuolar structures that correspond to macropinosomes in epithelial cells and fibroblasts. Overexpression of Rabankyrin-5 increases the number of macropinosomes and stimulates fluid-phase uptake, whereas its downregulation inhibits these processes. In polarised epithelial cells, this function is primarily restricted to the apical membrane. Rabankyrin-5 localises to large pinocytic structures underneath the apical surface of kidney proximal tubule cells, and its overexpression in polarised Madin-Darby canine kidney cells stimulates apical but not basolateral, non-clathrin-mediated pinocytosis. In demonstrating a regulatory role in endosome fusion and (macro)pinocytosis, our studies suggest that Rab5 regulates and coordinates different endocytic mechanisms through its effector Rabankyrin-5. Furthermore, its active role in apical pinocytosis in epithelial cells suggests an important function of Rabankyrin-5 in the physiology of polarised cells. |
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