title: OCRL controls trafficking through early endosomes via PtdIns4,5P₂-dependent regulation of endosomal actin.
abstract: Mutations in the phosphatidylinositol 4,5-bisphosphate (PtdIns4,5P(2)) 5-phosphatase OCRL cause Lowe syndrome, which is characterised by congenital cataracts, central hypotonia, and renal proximal tubular dysfunction. Previous studies have shown that OCRL interacts with components of the endosomal machinery; however, its role in endocytosis, and thus the pathogenic mechanisms of Lowe syndrome, have remained elusive. Here, we show that via its 5-phosphatase activity, OCRL controls early endosome (EE) function. OCRL depletion impairs the recycling of multiple classes of receptors, including megalin (which mediates protein reabsorption in the kidney) that are retained in engorged EEs. These trafficking defects are caused by ectopic accumulation of PtdIns4,5P(2) in EEs, which in turn induces an N-WASP-dependent increase in endosomal F-actin. Our data provide a molecular explanation for renal proximal tubular dysfunction in Lowe syndrome and highlight that tight control of PtdIns4,5P(2) and F-actin at the EEs is essential for exporting cargoes that transit this compartment.
authors.affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.
authors.forename: Mariella
authors.initials: M
authors.lastname: Vicinanza
authors.forename: Antonella
authors.initials: A
authors.lastname: Di Campli
authors.forename: Elena
authors.initials: E
authors.lastname: Polishchuk
authors.forename: Michele
authors.initials: M
authors.lastname: Santoro
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Tullio
authors.forename: Anna
authors.initials: A
authors.lastname: Godi
authors.forename: Elena
authors.initials: E
authors.lastname: Levtchenko
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: De Leo
authors.forename: Roman
authors.initials: R
authors.lastname: Polishchuk
authors.forename: Lisette
authors.initials: L
authors.lastname: Sandoval
authors.forename: Maria-Paz
authors.initials: MP
authors.lastname: Marzolo
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: De Matteis
mesh_terms: D000199:Actins / Q000378:metabolism*; D001692:Biological Transport; D002384:Catalysis; D002460:Cell Line; D004705:Endocytosis; D011992:Endosomes / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism; D009800:Oculocerebrorenal Syndrome / Q000235:genetics / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D058105:Polymerization
chemical_list: D000199:Actins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D019269:Phosphatidylinositol 4,5-Diphosphate; D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human