Lowe syndrome protein OCRL1 interacts with clathrin and regulates protein trafficking between endosomes and the trans-Golgi network

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 s...

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Bibliographic Details
Published in:Molecular biology of the cell 2005-08, Vol.16 (8), p.3467-3479
Main Authors: Choudhury, Rawshan, Diao, Aipo, Zhang, Fang, Eisenberg, Evan, Saint-Pol, Agnes, Williams, Catrin, Konstantakopoulos, Athanasios, Lucocq, John, Johannes, Ludger, Rabouille, Catherine, Greene, Lois E, Lowe, Martin
Format: Article
Language:English
Subjects:
Animals
Cell Line
Cell Membrane - metabolism
Cercopithecus aethiops
Clathrin - metabolism
Cryoelectron Microscopy
Endosomes - drug effects
Endosomes - metabolism
Humans
Membrane Glycoproteins - metabolism
Oculocerebrorenal Syndrome - genetics
Phosphoric Monoester Hydrolases - genetics
Phosphoric Monoester Hydrolases - metabolism
Protein Binding
Protein Transport
Receptor, IGF Type 2 - metabolism
RNA Interference
Shiga Toxin - pharmacology
trans-Golgi Network - drug effects
trans-Golgi Network - metabolism
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Summary: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.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E05-02-0120