title: Sac2/INPP5F is an inositol 4-phosphatase that functions in the endocytic pathway.
abstract: The recruitment of inositol phosphatases to endocytic membranes mediates dephosphorylation of PI(4,5)P2, a phosphoinositide concentrated in the plasma membrane, and prevents its accumulation on endosomes. The importance of the conversion of PI(4,5)P2 to PtdIns during endocytosis is demonstrated by the presence of both a 5-phosphatase and a 4-phosphatase (Sac domain) module in the synaptojanins, endocytic PI(4,5)P2 phosphatases conserved from yeast to humans and the only PI(4,5)P2 phosphatases in yeast. OCRL, another 5-phosphatase that couples endocytosis to PI(4,5)P2 dephosphorylation, lacks a Sac domain. Here we show that Sac2/INPP5F is a PI4P phosphatase that colocalizes with OCRL on endocytic membranes, including vesicles formed by clathrin-mediated endocytosis, macropinosomes, and Rab5 endosomes. An OCRL-Sac2/INPP5F interaction could be demonstrated by coimmunoprecipitation and was potentiated by Rab5, whose activity is required to recruit Sac2/INPP5F to endosomes. Sac2/INPP5F and OCRL may cooperate in the sequential dephosphorylation of PI(4,5)P2 at the 5 and 4 position of inositol in a partnership that mimics that of the two phosphatase modules of synaptojanin.
authors: Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510 Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510 Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510.
authors: Fubito
authors: F
authors: Nakatsu
authors: Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510 Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510 Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510.
authors: Mirko
authors: M
authors: Messa
authors: Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510 Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510 Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510.
authors: Ramiro
authors: R
authors: Nández
authors: Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510 Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510 Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510.
authors: Heather
authors: H
authors: Czapla
authors: Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510 Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510.
authors: Yixiao
authors: Y
authors: Zou
authors: Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510 Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510.
authors: Stephen M
authors: SM
authors: Strittmatter
authors: Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510 Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510 Department of Cell Biology, Howard Hughes Medical Institute, Department of Neurology, and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510 pietro.decamilli@yale.edu.
authors: Pietro
authors: P
authors: De Camilli
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004705:Endocytosis; D011992:Endosomes / Q000201:enzymology*; D057809:HEK293 Cells; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D018345:Mice, Knockout; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D010744:Phosphoric Monoester Hydrolases; C489581:Ocrl protein, mouse; C000606431:INPP5F protein, human; D000072181:Inositol Polyphosphate 5-Phosphatases; D020696:rab5 GTP-Binding Proteins