title: A phosphoinositide conversion mechanism for exit from endosomes.
abstract: Phosphoinositides are a minor class of short-lived membrane phospholipids that serve crucial functions in cell physiology ranging from cell signalling and motility to their role as signposts of compartmental membrane identity. Phosphoinositide 4-phosphates such as phosphatidylinositol 4-phosphate (PI(4)P) and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) are concentrated at the plasma membrane, on secretory organelles, and on lysosomes, whereas phosphoinositide 3-phosphates, most notably phosphatidylinositol 3-phosphate (PI(3)P), are a hallmark of the endosomal system. Directional membrane traffic between endosomal and secretory compartments, although inherently complex, therefore requires regulated phosphoinositide conversion. The molecular mechanism underlying this conversion of phosphoinositide identity during cargo exit from endosomes by exocytosis is unknown. Here we report that surface delivery of endosomal cargo requires hydrolysis of PI(3)P by the phosphatidylinositol 3-phosphatase MTM1, an enzyme whose loss of function leads to X-linked centronuclear myopathy (also called myotubular myopathy) in humans. Removal of endosomal PI(3)P by MTM1 is accompanied by phosphatidylinositol 4-kinase-2α (PI4K2α)-dependent generation of PI(4)P and recruitment of the exocyst tethering complex to enable membrane fusion. Our data establish a mechanism for phosphoinositide conversion from PI(3)P to PI(4)P at endosomes en route to the plasma membrane and suggest that defective phosphoinositide conversion at endosomes underlies X-linked centronuclear myopathy caused by mutation of MTM1 in humans.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Ketel
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Krauss
authors.affiliation: Department of Translational Medicine and Neurogenetics, Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Strasbourg University, 67404 Illkirch, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Nicot
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Puchkov
authors.affiliation: Freie Universität Berlin, Faculty of Biology, Chemistry and Pharmacy, 14195 Berlin, Germany.
authors.forename: Marnix
authors.initials: M
authors.lastname: Wieffer
authors.affiliation: European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics Unit, 69117 Heidelberg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Müller
authors.affiliation: European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics Unit, 69117 Heidelberg, Germany.
authors.forename: Devaraj
authors.initials: D
authors.lastname: Subramanian
authors.affiliation: European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics Unit, 69117 Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz
authors.affiliation: Department of Translational Medicine and Neurogenetics, Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Strasbourg University, 67404 Illkirch, France.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany.|Freie Universität Berlin, Faculty of Biology, Chemistry and Pharmacy, 14195 Berlin, Germany.|NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Haucke
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D005089:Exocytosis; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D008561:Membrane Fusion; D020914:Myopathies, Structural, Congenital / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; C037178:phosphatidylinositol 4-phosphate; C483312:phosphoinositide 3-phosphate; D019870:1-Phosphatidylinositol 4-Kinase; D010744:Phosphoric Monoester Hydrolases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin; C061816:phosphatidylinositol-3-phosphatase