title: Identification of a feedback loop involving β-glucosidase 2 and its product sphingosine sheds light on the molecular mechanisms in Gaucher disease.
abstract: The lysosomal acid β-glucosidase GBA1 and the non-lysosomal β-glucosidase GBA2 degrade glucosylceramide (GlcCer) to glucose and ceramide in different cellular compartments. Loss of GBA2 activity and the resulting accumulation of GlcCer results in male infertility, whereas mutations in theGBA1gene and loss of GBA1 activity cause the lipid-storage disorder Gaucher disease. However, the role of GBA2 in Gaucher disease pathology and its relationship to GBA1 is not well understood. Here, we report a GBA1-dependent down-regulation of GBA2 activity in patients with Gaucher disease. Using an experimental approach combining cell biology, biochemistry, and mass spectrometry, we show that sphingosine, the cytotoxic metabolite accumulating in Gaucher cells through the action of GBA2, directly binds to GBA2 and inhibits its activity. We propose a negative feedback loop, in which sphingosine inhibits GBA2 activity in Gaucher cells, preventing further sphingosine accumulation and, thereby, cytotoxicity. Our findings add a new chapter to the understanding of the complex molecular mechanism underlying Gaucher disease and the regulation of β-glucosidase activity in general.
authors.affiliation: From the Minerva Max Planck Research Group, Molecular Physiology, and.
authors.forename: Sophie
authors.initials: S
authors.lastname: Schonauer
authors.affiliation: the Department of Molecular Sensory Systems, Center of Advanced European Studies and Research (caesar), 53175 Bonn, Germany.
authors.forename: Heinz G
authors.initials: HG
authors.lastname: Körschen
authors.affiliation: the Department of Cell Biology of Lipids, LIMES Institute, University of Bonn, Bonn, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Penno
authors.affiliation: the Department of Molecular Sensory Systems, Center of Advanced European Studies and Research (caesar), 53175 Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rennhack
authors.affiliation: the LIMES Institute, c/o Kekulé-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Breiden
authors.affiliation: the LIMES Institute, c/o Kekulé-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Sandhoff
authors.affiliation: the Institute of Molecular Physiology and Biotechnology of Plants, University of Bonn, 53115 Bonn, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Gutbrod
authors.affiliation: the Institute of Molecular Physiology and Biotechnology of Plants, University of Bonn, 53115 Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Dörmann
authors.affiliation: From the Minerva Max Planck Research Group, Molecular Physiology, and.
authors.forename: Diana N
authors.initials: DN
authors.lastname: Raju
authors.affiliation: the Proteomic Core Facility, EMBL Heidelberg, 69117 Heidelberg, Germany.
authors.forename: Per
authors.initials: P
authors.lastname: Haberkant
authors.affiliation: the Biochemie-Zentrum (BZH), Ruprecht-Karls-University Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Mathias J
authors.initials: MJ
authors.lastname: Gerl
authors.affiliation: the Biochemie-Zentrum (BZH), Ruprecht-Karls-University Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Brügger
authors.affiliation: the Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel, and.
authors.forename: Hila
authors.initials: H
authors.lastname: Zigdon
authors.affiliation: the Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel, and.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Vardi
authors.affiliation: the Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel, and.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
authors.affiliation: the Department of Cell Biology of Lipids, LIMES Institute, University of Bonn, Bonn, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiele
authors.affiliation: From the Minerva Max Planck Research Group, Molecular Physiology, and dagmar.wachten@caesar.de.|the Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wachten
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D005776:Gaucher Disease / Q000201:enzymology* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D005962:Glucosylceramidase; D005963:Glucosylceramides / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008954:Models, Biological; D013110:Sphingosine / Q000235:genetics / Q000378:metabolism*; D001617:beta-Glucosidase / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D005963:Glucosylceramides; D001617:beta-Glucosidase; C517538:beta-glucosidase 2, mouse; C517537:GBA2 protein, human; D005962:Glucosylceramidase; D013110:Sphingosine
keywords: Gaucher disease; glycerosphingolipid; lipid metabolism; lipid signaling; lipid-protein interaction