title: Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase.
abstract: Gaucher disease is a lysosomal storage disorder caused by a defect in the degradation of glucosylceramide catalyzed by the lysosomal enzyme β-glucocerebrosidase (GBA). GBA reaches lysosomes via association with its receptor, lysosomal integral membrane protein type 2 (LIMP-2). We found that distinct phosphatidylinositol 4-kinases (PI4Ks) play important roles at multiple steps in the trafficking pathway of the LIMP-2/GBA complex. Acute depletion of phosphatidylinositol 4-phosphate in the Golgi caused accumulation of LIMP-2 in this compartment, and PI4KIIIβ was found to be responsible for controlling the exit of LIMP-2 from the Golgi. In contrast, depletion of PI4KIIα blocked trafficking at a post-Golgi compartment, leading to accumulation of LIMP-2 in enlarged endosomal vesicles. PI4KIIα depletion also caused secretion of missorted GBA into the medium, which was attenuated by limiting LIMP-2/GBA exit from the Golgi by PI4KIIIβ inhibitors. These studies identified PI4KIIIβ and PI4KIIα as important regulators of lysosomal delivery of GBA, revealing a new element of control to sphingolipid homeostasis by phosphoinositides.
authors.affiliation: Section on Molecular Signal Transduction, Program for Developmental Neuroscience, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Marko
authors.initials: M
authors.lastname: Jović
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Kean
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Szentpetery
authors.forename: Gordon
authors.initials: G
authors.lastname: Polevoy
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.forename: Julie A
authors.initials: JA
authors.lastname: Brill
authors.forename: Tamas
authors.initials: T
authors.lastname: Balla
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D011992:Endosomes / Q000378:metabolism; D005776:Gaucher Disease / Q000201:enzymology / Q000378:metabolism; D005962:Glucosylceramidase / Q000378:metabolism*; D006056:Golgi Apparatus / Q000201:enzymology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D052119:Lysosomal-Associated Membrane Protein 2; D015778:Minor Histocompatibility Antigens; D034741:RNA, Small Interfering; D017853:Phosphotransferases (Alcohol Group Acceptor); D019870:1-Phosphatidylinositol 4-Kinase; C402182:phosphatidylinositol phosphate 4-kinase; D005962:Glucosylceramidase