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Vol. 16, Issue 8, 3467-3479, August 2005
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* Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom;
Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
Traffic and Signaling Laboratory, Department of Cellular Compartmentalization and Dynamics, Unité Mixte Recherche 144 Curie/Centre National de la Recherche Scientifique, Curie Institute, F-75248 Paris Cedex 05, France;
|| Universitair Medisch Centrum Utrecht, Department of Cell Biology, AZU, 3584 CX Utrecht, The Netherlands; and
School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom
Submitted February 11, 2005;
Revised May 9, 2005;
Accepted May 12, 2005
Monitoring Editor: Sean Munro
Oculocerebrorenal syndrome of Lowe is caused by mutation of OCRL1, a phosphatidylinositol 4,5-bisphosphate 5-phosphatase localized at the Golgi apparatus. The cellular role of OCRL1 is unknown, and consequently the mechanism by which loss of OCRL1 function leads to disease is ill defined. Here, we show that OCRL1 is associated with clathrin-coated transport intermediates operating between the trans-Golgi network (TGN) and endosomes. OCRL1 interacts directly with clathrin heavy chain and promotes clathrin assembly in vitro. Interaction with clathrin is not, however, required for membrane association of OCRL1. Overexpression of OCRL1 results in redistribution of clathrin and the cation-independent mannose 6-phosphate receptor (CI-MPR) to enlarged endosomal structures that are defective in retrograde trafficking to the TGN. Depletion of cellular OCRL1 also causes partial redistribution of a CI-MPR reporter to early endosomes. These findings suggest a role for OCRL1 in clathrin-mediated trafficking of proteins from endosomes to the TGN and that defects in this pathway might contribute to the Lowe syndrome phenotype.
Abbreviations used: CI-MPR, cation-independent mannose 6-phosphate receptor; EEA1, early endosome-associated antigen 1; FRAP, fluorescence recovery after photobleaching; OCRL1, oculocerebrorenal syndrome of Lowe protein 1; siRNA, small interfering RNA; STXB, Shiga toxin B subunit; TfR, transferrin receptor.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
Address correspondence to: Martin Lowe (martin.lowe{at}manchester.ac.uk).
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