TY - JOUR TI - A role of OCRL in clathrin-coated pit dynamics and uncoating revealed by studies of Lowe syndrome cells AU - Nández, Ramiro AU - Balkin, Daniel M AU - Messa, Mirko AU - Liang, Liang AU - Paradise, Summer AU - Czapla, Heather AU - Hein, Marco Y AU - Duncan, James S AU - Mann, Matthias AU - De Camilli, Pietro A2 - Pfeffer, Suzanne R VL - 3 PY - 2014 DA - 2014/08/08 SP - e02975 C1 - eLife 2014;3:e02975 DO - 10.7554/eLife.02975 UR - https://doi.org/10.7554/eLife.02975 AB - Mutations in the inositol 5-phosphatase OCRL cause Lowe syndrome and Dent's disease. Although OCRL, a direct clathrin interactor, is recruited to late-stage clathrin-coated pits, clinical manifestations have been primarily attributed to intracellular sorting defects. Here we show that OCRL loss in Lowe syndrome patient fibroblasts impacts clathrin-mediated endocytosis and results in an endocytic defect. These cells exhibit an accumulation of clathrin-coated vesicles and an increase in U-shaped clathrin-coated pits, which may result from sequestration of coat components on uncoated vesicles. Endocytic vesicles that fail to lose their coat nucleate the majority of the numerous actin comets present in patient cells. SNX9, an adaptor that couples late-stage endocytic coated pits to actin polymerization and which we found to bind OCRL directly, remains associated with such vesicles. These results indicate that OCRL acts as an uncoating factor and that defects in clathrin-mediated endocytosis likely contribute to pathology in patients with OCRL mutations. KW - clathrin-mediated endocytosis KW - uncoating KW - Lowe syndrome KW - PI(4,5)P2 KW - SNX9 KW - actin comet JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -