title: Lowe syndrome protein OCRL1 interacts with clathrin and regulates protein trafficking between endosomes and the trans-Golgi network.
abstract: 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.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Rawshan
authors.initials: R
authors.lastname: Choudhury
authors.forename: Aipo
authors.initials: A
authors.lastname: Diao
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.forename: Evan
authors.initials: E
authors.lastname: Eisenberg
authors.forename: Agnes
authors.initials: A
authors.lastname: Saint-Pol
authors.forename: Catrin
authors.initials: C
authors.lastname: Williams
authors.forename: Athanasios
authors.initials: A
authors.lastname: Konstantakopoulos
authors.forename: John
authors.initials: J
authors.lastname: Lucocq
authors.forename: Ludger
authors.initials: L
authors.lastname: Johannes
authors.forename: Catherine
authors.initials: C
authors.lastname: Rabouille
authors.forename: Lois E
authors.initials: LE
authors.lastname: Greene
authors.forename: Martin
authors.initials: M
authors.lastname: Lowe
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D002966:Clathrin / Q000378:metabolism*; D020285:Cryoelectron Microscopy; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D009800:Oculocerebrorenal Syndrome / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D034622:RNA Interference; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D022621:Shiga Toxin / Q000494:pharmacology; D021601:trans-Golgi Network / Q000187:drug effects / Q000378:metabolism*
chemical_list: D002966:Clathrin; D008562:Membrane Glycoproteins; D017527:Receptor, IGF Type 2; C072237:TGOLN2 protein, human; D022621:Shiga Toxin; D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human