title: Phosphoinositides Regulate Ciliary Protein Trafficking to Modulate Hedgehog Signaling.
abstract: Primary cilia interpret vertebrate Hedgehog (Hh) signals. Why cilia are essential for signaling is unclear. One possibility is that some forms of signaling require a distinct membrane lipid composition, found at cilia. We found that the ciliary membrane contains a particular phosphoinositide, PI(4)P, whereas a different phosphoinositide, PI(4,5)P2, is restricted to the membrane of the ciliary base. This distribution is created by Inpp5e, a ciliary phosphoinositide 5-phosphatase. Without Inpp5e, ciliary PI(4,5)P2 levels are elevated and Hh signaling is disrupted. Inpp5e limits the ciliary levels of inhibitors of Hh signaling, including Gpr161 and the PI(4,5)P2-binding protein Tulp3. Increasing ciliary PI(4,5)P2 levels or conferring the ability to bind PI(4)P on Tulp3 increases the ciliary localization of Tulp3. Lowering Tulp3 in cells lacking Inpp5e reduces ciliary Gpr161 levels and restores Hh signaling. Therefore, Inpp5e regulates ciliary membrane phosphoinositide composition, and Tulp3 reads out ciliary phosphoinositides to control ciliary protein localization, enabling Hh signaling.
authors: Department of Biochemistry and Biophysics and Cardiovascular Research Institute, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA.
authors: Francesc R
authors: FR
authors: Garcia-Gonzalo
authors: Department of Cell Biology and Center for Cell Dynamics, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors: Siew C
authors: SC
authors: Phua
authors: Department of Biochemistry and Biophysics and Cardiovascular Research Institute, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA.
authors: Elle C
authors: EC
authors: Roberson
authors: Department of Biochemistry and Biophysics and Cardiovascular Research Institute, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA.
authors: Galo
authors: G
authors: Garcia
authors: Department of Biochemistry and Biophysics and Cardiovascular Research Institute, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA.
authors: Monika
authors: M
authors: Abedin
authors: Laboratory of Functional Genetics, GIGA-Research Centre, Université de Liège, 4000-Liège, Belgium.
authors: Stéphane
authors: S
authors: Schurmans
authors: Department of Cell Biology and Center for Cell Dynamics, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors: Takanari
authors: T
authors: Inoue
authors: Department of Biochemistry and Biophysics and Cardiovascular Research Institute, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA.
authors: Jeremy F
authors: JF
authors: Reiter
mesh_terms: D000818:Animals; D002923:Cilia / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D003598:Cytoskeletal Proteins; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D010744:Phosphoric Monoester Hydrolases; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; D000099182:Phosphoinositide 5-Phosphatases; C533095:GPR161 protein, mouse; C485499:Tulp3 protein, mouse; C037178:phosphatidylinositol 4-phosphate