Abstract
Mutations of the inositol-5-phosphatase OCRL cause Lowe syndrome and Dent-II disease. Both are rare genetic disorders characterized by renal defects. Lowe syndrome is furthermore characterized by defects of the eye (congenital cataracts) and nervous system (mental disabilities, hypotonia). OCRL has been localised to various endocytic compartments suggesting impairments in the endocytic pathway as possible disease mechanism. Recent evidence strongly supports this view and shows essential roles of OCRL at clathrin coated pits, transport of cargo from endosomes to the trans-Golgi network as well as recycling of receptors from endosomes to the plasma membrane. In particular in vitro and in vivo evidence demonstrates an important role of OCRL in recycling of megalin, a multi-ligand receptor crucial for reabsorption of nutrients in the proximal tubulus, a process severely impaired in Lowe syndrome patients. Thus defects in the endocytic pathway are likely to significantly contribute to the kidney phenotype in Lowe syndrome and Dent-II disease.
Acknowledgments
We would like to thank Dr. Martin Lowe (University of Manchester, UK) for critical reading of the manuscript. This work was supported by a Marie Curie career integration grant (CIG) ‘Endosignal’ to K.S.E.
References
Astle, M.V., Horan, K.A., Ooms, L.M., and Mitchell, C.A. (2007). The inositol polyphosphate 5-phosphatases: traffic controllers, waistline watchers and tumour suppressors? Biochem. Soc. Symp. 161–181.Search in Google Scholar
Attree, O., Olivos, I.M., Okabe, I., Bailey, L.C., Nelson, D.L., Lewis, R.A., McInnes, R.R., and Nussbaum, R.L. (1992). The Lowe’s oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase. Nature 358, 239–242.10.1038/358239a0Search in Google Scholar
Choudhury, R., Diao, A., Zhang, F., Eisenberg, E., Saint-Pol, A., Williams, C., Konstantakopoulos, A., Lucocq, J., Johannes, L., Rabouille, C., et al. (2005). Lowe syndrome protein OCRL1 interacts with clathrin and regulates protein trafficking between endosomes and the trans-Golgi network. Mol. Biol. Cell 16, 3467–3479.10.1091/mbc.e05-02-0120Search in Google Scholar
Choudhury, R., Noakes, C.J., McKenzie, E., Kox, C., and Lowe, M. (2009). Differential clathrin binding and subcellular localization of OCRL1 splice isoforms. J. Biol. Chem. 284, 9965–9973.10.1074/jbc.M807442200Search in Google Scholar
Coon, B.G., Hernandez, V., Madhivanan, K., Mukherjee, D., Hanna, C.B., Barinaga-Rementeria Ramirez, I., Lowe, M., Beales, P.L., and Aguilar, R.C. (2012). The Lowe syndrome protein OCRL1 is involved in primary cilia assembly. Hum. Mol. Genet. 21, 1835–1847.10.1093/hmg/ddr615Search in Google Scholar
Cremona, O., Di Paolo, G., Wenk, M.R., Luthi, A., Kim, W.T., Takei, K., Daniell, L., Nemoto, Y., Shears, S.B., Flavell, R.A., et al. (1999). Essential role of phosphoinositide metabolism in synaptic vesicle recycling. Cell 99, 179–188.10.1016/S0092-8674(00)81649-9Search in Google Scholar
Cui, S., Guerriero, C.J., Szalinski, C.M., Kinlough, C.L., Hughey, R.P., and Weisz, O.A. (2010). OCRL1 function in renal epithelial membrane traffic. Am. J. Physiol. Renal Physiol. 298, F335–345.10.1152/ajprenal.00453.2009Search in Google Scholar PubMed PubMed Central
Di Paolo, G. and De Camilli, P. (2006). Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651–657.10.1038/nature05185Search in Google Scholar PubMed
Dressman, M.A., Olivos-Glander, I.M., Nussbaum, R.L., and Suchy, S.F. (2000). Ocrl1, a PtdIns(4,5)P(2) 5-phosphatase, is localized to the trans-Golgi network of fibroblasts and epithelial cells. J. Histochem. Cytochem. 48, 179–190.10.1177/002215540004800203Search in Google Scholar PubMed
Dyson, J.M., Fedele, C.G., Davies, E.M., Becanovic, J., and Mitchell, C.A. (2012). Phosphoinositide phosphatases: just as important as the kinases. Subcell. Biochem. 58, 215–279.10.1007/978-94-007-3012-0_7Search in Google Scholar PubMed
Erdmann, K.S., Mao, Y., McCrea, H.J., Zoncu, R., Lee, S., Paradise, S., Modregger, J., Biemesderfer, D., Toomre, D., and De Camilli, P. (2007). A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway. Dev. Cell 13, 377–390.10.1016/j.devcel.2007.08.004Search in Google Scholar PubMed PubMed Central
Falguieres, T., Mallard, F., Baron, C., Hanau, D., Lingwood, C., Goud, B., Salamero, J., and Johannes, L. (2001). Targeting of Shiga toxin B-subunit to retrograde transport route in association with detergent-resistant membranes. Mol. Biol. Cell 12, 2453–2468.10.1091/mbc.12.8.2453Search in Google Scholar PubMed PubMed Central
Faucherre, A., Desbois, P., Nagano, F., Satre, V., Lunardi, J., Gacon, G., and Dorseuil, O. (2005). Lowe syndrome protein Ocrl1 is translocated to membrane ruffles upon Rac GTPase activation: a new perspective on Lowe syndrome pathophysiology. Hum. Mol. Genet. 14, 1441–1448.10.1093/hmg/ddi153Search in Google Scholar PubMed
Ferguson, S.M., Raimondi, A., Paradise, S., Shen, H., Mesaki, K., Ferguson, A., Destaing, O., Ko, G., Takasaki, J., Cremona, O., et al. (2009). Coordinated actions of actin and BAR proteins upstream of dynamin at endocytic clathrin-coated pits. Dev. Cell 17, 811–822.10.1016/j.devcel.2009.11.005Search in Google Scholar PubMed PubMed Central
Grieve, A.G., Daniels, R.D., Sanchez-Heras, E., Hayes, M.J., Moss, S.E., Matter, K., Lowe, M., and Levine, T.P. (2011). Lowe Syndrome protein OCRL1 supports maturation of polarized epithelial cells. PLoS One 6, e24044.10.1371/journal.pone.0024044Search in Google Scholar PubMed PubMed Central
Hoopes, R.R. Jr., Shrimpton, A.E., Knohl, S.J., Hueber, P., Hoppe, B., Matyus, J., Simckes, A., Tasic, V., Toenshoff, B., Suchy, S.F., et al. (2005). Dent Disease with mutations in OCRL1. Am. J. Hum. Genet. 76, 260–267.10.1086/427887Search in Google Scholar PubMed PubMed Central
Hou, X., Hagemann, N., Schoebel, S., Blankenfeldt, W., Goody, R.S., Erdmann, K.S., and Itzen, A. (2011). A structural basis for Lowe syndrome caused by mutations in the Rab-binding domain of OCRL1. EMBO J. 30, 1659–1670.10.1038/emboj.2011.60Search in Google Scholar PubMed PubMed Central
Hsu, F., Hu, F., and Mao, Y. (2015). Spatiotemporal control of phosphatidylinositol 4-phosphate by Sac2 regulates endocytic recycling. J. Cell. Biol. 209, 97–110.10.1083/jcb.201408027Search in Google Scholar PubMed PubMed Central
Hyvola, N., Diao, A., McKenzie, E., Skippen, A., Cockcroft, S., and Lowe, M. (2006). Membrane targeting and activation of the Lowe syndrome protein OCRL1 by rab GTPases. EMBO J. 25, 3750–3761.10.1038/sj.emboj.7601274Search in Google Scholar PubMed PubMed Central
Johnson, J.M., Castle, J., Garrett-Engele, P., Kan, Z., Loerch, P.M., Armour, C.D., Santos, R., Schadt, E.E., Stoughton, R., and Shoemaker, D.D. (2003). Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science 302, 2141–2144.10.1126/science.1090100Search in Google Scholar PubMed
Kramer-Zucker, A.G., Olale, F., Haycraft, C.J., Yoder, B.K., Schier, A.F., and Drummond, I.A. (2005). Cilia-driven fluid flow in the zebrafish pronephros, brain and Kupffer’s vesicle is required for normal organogenesis. Development 132, 1907–1921.10.1242/dev.01772Search in Google Scholar PubMed
Liu, J., Kaksonen, M., Drubin, D.G., and Oster, G. (2006). Endocytic vesicle scission by lipid phase boundary forces. Proc. Natl. Acad. Sci. USA 103, 10277–10282.10.1073/pnas.0601045103Search in Google Scholar
Liu, J., Sun, Y., Drubin, D.G., and Oster, G.F. (2009). The mechanochemistry of endocytosis. PLoS Biol. 7, e1000204.10.1371/journal.pbio.1000204Search in Google Scholar
Lundmark, R. and Carlsson, S.R. (2009). SNX9 – a prelude to vesicle release. J. Cell Sci. 122, 5–11.10.1242/jcs.037135Search in Google Scholar
Mao, Y., Balkin, D.M., Zoncu, R., Erdmann, K.S., Tomasini, L., Hu, F., Jin, M.M., Hodsdon, M.E., and P. De Camilli (2009). A PH domain within OCRL bridges clathrin-mediated membrane trafficking to phosphoinositide metabolism. EMBO J. 28, 1831–1842.10.1038/emboj.2009.155Search in Google Scholar
Mehta, Z.B., Pietka, G., and Lowe, M. (2014). The cellular and physiological functions of the Lowe syndrome protein OCRL1. Traffic 15, 471–487.10.1111/tra.12160Search in Google Scholar
Miaczynska, M., Christoforidi, S.S, Giner, A., Shevchenko, A., Uttenweiler-Joseph, S., Habermann, B., Wilm, M., Parton, R.G., and Zerial, M. (2004). APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment. Cell 116, 445–456.10.1016/S0092-8674(04)00117-5Search in Google Scholar
Nakatsu, F., Messa, M., Nandez, R., Czapla, H., Zou, Y., Strittmatter, S.M., and De Camilli, P. (2015). Sac2/INPP5F is an inositol 4-phosphatase that functions in the endocytic pathway. J. Cell. Biol. 209, 85–95.10.1083/jcb.201409064Search in Google Scholar PubMed PubMed Central
Nandez, R., Balkin, D.M., Messa, M., Liang, L., Paradise, S., Czapla, H., Hein, M.Y., Duncan, J.S., Mann, M., and De Camilli, P. (2014). A role of OCRL in clathrin-coated pit dynamics and uncoating revealed by studies of Lowe syndrome cells. Elife 3, e02975.10.7554/eLife.02975.026Search in Google Scholar
Noakes, C.J., Lee, G., and Lowe, M. (2011). The PH domain proteins IPIP27A and B link OCRL1 to receptor recycling in the endocytic pathway. Mol. Biol. Cell 22, 606–623.10.1091/mbc.e10-08-0730Search in Google Scholar
Norden, A.G., Lapsley, M., Igarashi, T., Kelleher, C.L., Lee, P.J., Matsuyama, T., Scheinman, S.J., Shiraga, H., Sundin, D.P., Thakker, R.V., et al. (2002). Urinary megalin deficiency implicates abnormal tubular endocytic function in Fanconi syndrome. J. Am. Soc. Nephrol. 13, 125–133.10.1681/ASN.V131125Search in Google Scholar PubMed
Nussbaum, R.L., Orrison, B.M., Janne, P.A., Charnas, L., and Chinault, A.C. (1997). Physical mapping and genomic structure of the Lowe syndrome gene OCRL1. Hum. Genet. 99, 145–150.10.1007/s004390050329Search in Google Scholar PubMed
Olivos-Glander, I.M., Janne, P.A., and Nussbaum, R.L. (1995). The oculocerebrorenal syndrome gene product is a 105-kD protein localized to the Golgi complex. Am. J. Hum. Genet. 57, 817–823.Search in Google Scholar
Oltrabella, F., Pietka, G., Ramirez, I.B., Mironov, A., Starborg, T., Drummond, I.A., Hinchliffe, K.A., and Lowe, M. (2015). The Lowe syndrome protein OCRL1 is required for endocytosis in the zebrafish pronephric tubule. PLoS Genet. 11, e1005058.10.1371/journal.pgen.1005058Search in Google Scholar PubMed PubMed Central
Ooms, L.M., Horan, K.A., Rahman, P., Seaton, G., Gurung, R., Kethesparan, D.S., and Mitchell, C.A. (2009). The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease. Biochem. J. 419, 29–49.10.1042/BJ20081673Search in Google Scholar PubMed
Pirruccello, M. and P. De Camilli (2012). Inositol 5-phosphatases: insights from the Lowe syndrome protein OCRL. Trends Biochem. Sci. 37, 134–143.10.1016/j.tibs.2012.01.002Search in Google Scholar PubMed PubMed Central
Pirruccello, M., Swan, L.E., Folta-Stogniew, E., and De Camilli, P. (2011). Recognition of the F&H motif by the Lowe syndrome protein OCRL. Nat. Struct. Mol. Biol. 18, 789–795.10.1038/nsmb.2071Search in Google Scholar PubMed PubMed Central
Posor, Y., Eichhorn-Gruenig, M., Puchkov, D., Schoneberg, J., Ullrich, A., Lampe, A., Muller, R., Zarbakhsh, S., Gulluni, F., Hirsch, E., et al. (2013). Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate. Nature 499, 233–237.10.1038/nature12360Search in Google Scholar PubMed
Raghavan, V., Rbaibi, Y., Pastor-Soler, N.M., Carattino, M.D., and Weisz, O.A. (2014). Shear stress-dependent regulation of apical endocytosis in renal proximal tubule cells mediated by primary cilia. Proc. Natl. Acad. Sci. USA 111, 8506–8511.10.1073/pnas.1402195111Search in Google Scholar PubMed PubMed Central
Ramirez, I.B., Pietka, G., Jones, D.R., Divecha, N., Alia, A., Baraban, S.C., Hurlstone, A.F., and Lowe, M. (2012). Impaired neural development in a zebrafish model for Lowe syndrome. Hum. Mol. Genet. 21, 1744–1759.10.1093/hmg/ddr608Search in Google Scholar PubMed PubMed Central
Schmid, A.C., Wise, H.M., Mitchell, C.A., Nussbaum, R., and Woscholski, R. (2004). Type II phosphoinositide 5-phosphatases have unique sensitivities towards fatty acid composition and head group phosphorylation. FEBS Lett 576, 9–13.10.1016/j.febslet.2004.08.052Search in Google Scholar PubMed
Schurman, S.J. and Scheinman, S.J. (2009). Inherited cerebrorenal syndromes. Nat. Rev. Nephrol. 5, 529–538.10.1038/nrneph.2009.124Search in Google Scholar PubMed
Shin, H.W., Hayashi, M., Christoforidis, S., Lacas-Gervais, S., Hoepfner, S., Wenk, M.R., Modregger, J., Uttenweiler-Joseph, S., Wilm, M., Nystuen, A., et al. (2005). An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway. J. Cell. Biol. 170, 607–618.10.1083/jcb.200505128Search in Google Scholar PubMed PubMed Central
Suchy, S.F., Olivos-Glander, I.M., and Nussabaum, R.L. (1995). Lowe syndrome, a deficiency of phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi apparatus. Hum. Mol. Genet. 4, 2245–2250.10.1093/hmg/4.12.2245Search in Google Scholar PubMed
Swan, L.E., Tomasini, L., Pirruccello, M., Lunardi, J., and De Camilli, P. (2010). Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1. Proc. Natl. Acad. Sci. USA 107, 3511–3516.10.1073/pnas.0914658107Search in Google Scholar PubMed PubMed Central
Taylor, M.J., Perrais, D., and Merrifield, C.J. (2011). A high precision survey of the molecular dynamics of mammalian clathrin-mediated endocytosis. PLoS Biol. 9, e1000604.10.1371/journal.pbio.1000604Search in Google Scholar PubMed PubMed Central
Ungewickell, A., Ward, M.E., Ungewickell, E., and Majerus, P.W. (2004). The inositol polyphosphate 5-phosphatase Ocrl associates with endosomes that are partially coated with clathrin. Proc. Natl. Acad. Sci. USA 101, 13501–13506.10.1073/pnas.0405664101Search in Google Scholar PubMed PubMed Central
Ungewickell, A.J. and Majerus, P.W. (1999). Increased levels of plasma lysosomal enzymes in patients with Lowe syndrome. Proc. Natl. Acad. Sci. USA 96, 13342–13344.10.1073/pnas.96.23.13342Search in Google Scholar PubMed PubMed Central
van Rahden, V.A., Brand, K., Najm, J., Heeren, J., Pfeffer, S.R., Braulke, T., and Kutsche, K. (2012). The 5-phosphatase OCRL mediates retrograde transport of the mannose 6-phosphate receptor by regulating a Rac1-cofilin signalling module. Hum. Mol. Genet. 21, 5019–5038.10.1093/hmg/dds343Search in Google Scholar PubMed PubMed Central
Vicinanza, M., D’Angelo, G., Di Campli, A., and De Matteis, M.A. (2008). Function and dysfunction of the PI system in membrane trafficking. EMBO J. 27, 2457–2470.10.1038/emboj.2008.169Search in Google Scholar PubMed PubMed Central
Vicinanza, M., Di Campli, A., Polishchuk, E., Santoro, M., Di Tullio, G., Godi, A., Levtchenko, E., De Leo, M.G., Polishchuk, R., Sandoval, et al. (2011). OCRL controls trafficking through early endosomes via PtdIns4,5P(2)-dependent regulation of endosomal actin. EMBO J. 30, 4970–4985.10.1038/emboj.2011.354Search in Google Scholar PubMed PubMed Central
Zhang, X., Jefferson, A.B., Auethavekiat, V., and Majerus, P.W. (1995). The protein deficient in Lowe syndrome is a phosphatidylinositol-4,5-bisphosphate 5-phosphatase. Proc. Natl. Acad. Sci. USA 92, 4853–4856.10.1073/pnas.92.11.4853Search in Google Scholar PubMed PubMed Central
Zoncu, R., Perera, R.M., Balkin, D.M., Pirruccello, M., Toomre, D., and De Camilli, P. (2009). A phosphoinositide switch controls the maturation and signaling properties of APPL endosomes. Cell 136, 1110–1121.10.1016/j.cell.2009.01.032Search in Google Scholar PubMed PubMed Central
©2015 by De Gruyter