title: Osh proteins regulate phosphoinositide metabolism at ER-plasma membrane contact sites.
abstract: Sac1 phosphoinositide (PI) phosphatases are essential regulators of PI-signaling networks. Yeast Sac1, an integral endoplasmic reticulum (ER) membrane protein, controls PI4P levels at the ER, Golgi, and plasma membrane (PM). Whether Sac1 can act in trans and turn over PI4P at the Golgi and PM from the ER remains a paradox. We find that Sac1-mediated PI4P metabolism requires the oxysterol-binding homology (Osh) proteins. The PH domain-containing family member, Osh3, localizes to PM/ER membrane contact sites dependent upon PM PI4P levels. We reconstitute Osh protein-stimulated Sac1 PI phosphatase activity in vitro. We also show that the ER membrane VAP proteins, Scs2/Scs22, control PM PI4P levels and Sac1 activity in vitro. We propose that Osh3 functions at ER/PM contact sites as both a sensor of PM PI4P and an activator of the ER Sac1 phosphatase. Our findings further suggest that the conserved Osh proteins control PI metabolism at additional membrane contact sites.
authors.affiliation: Weill Institute for Cell & Molecular Biology, Department of Molecular Biology & Genetics, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Stefan
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Manford
authors.forename: Daniel
authors.initials: D
authors.lastname: Baird
authors.forename: Jason
authors.initials: J
authors.lastname: Yamada-Hanff
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Mao
authors.forename: Scott D
authors.initials: SD
authors.lastname: Emr
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D000098825:Oxysterol Binding Proteins
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D018129:Phosphatidylinositol Phosphates; D010744:Phosphoric Monoester Hydrolases; D011987:Receptors, Steroid; D029701:Saccharomyces cerevisiae Proteins; C087901:KES1 protein, S cerevisiae; D000098825:Oxysterol Binding Proteins; C432936:OSH3 protein, S cerevisiae; C081864:SAC1 protein, S cerevisiae