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Identification of a feedback loop involving ß-glucosidase 2 and its product sphingosine sheds light on the molecular mechanisms in Gaucher disease.
Schonauer, Sophie; Körschen, Heinz G; Penno, Anke; Rennhack, Andreas; Breiden, Bernadette; Sandhoff, Konrad; Gutbrod, Katharina; Dörmann, Peter; Raju, Diana N; Haberkant, Per; Gerl, Mathias J; Brügger, Britta; Zigdon, Hila; Vardi, Ayelet; Futerman, Anthony H; Thiele, Christoph; Wachten, Dagmar.
Afiliación
  • Schonauer S; From the Minerva Max Planck Research Group, Molecular Physiology, and.
  • Körschen HG; the Department of Molecular Sensory Systems, Center of Advanced European Studies and Research (caesar), 53175 Bonn, Germany.
  • Penno A; the Department of Cell Biology of Lipids, LIMES Institute, University of Bonn, Bonn, Germany.
  • Rennhack A; the Department of Molecular Sensory Systems, Center of Advanced European Studies and Research (caesar), 53175 Bonn, Germany.
  • Breiden B; the LIMES Institute, c/o Kekulé-Institute, University of Bonn, 53115 Bonn, Germany.
  • Sandhoff K; the LIMES Institute, c/o Kekulé-Institute, University of Bonn, 53115 Bonn, Germany.
  • Gutbrod K; the Institute of Molecular Physiology and Biotechnology of Plants, University of Bonn, 53115 Bonn, Germany.
  • Dörmann P; the Institute of Molecular Physiology and Biotechnology of Plants, University of Bonn, 53115 Bonn, Germany.
  • Raju DN; From the Minerva Max Planck Research Group, Molecular Physiology, and.
  • Haberkant P; the Proteomic Core Facility, EMBL Heidelberg, 69117 Heidelberg, Germany.
  • Gerl MJ; the Biochemie-Zentrum (BZH), Ruprecht-Karls-University Heidelberg, 69120 Heidelberg, Germany.
  • Brügger B; the Biochemie-Zentrum (BZH), Ruprecht-Karls-University Heidelberg, 69120 Heidelberg, Germany.
  • Zigdon H; the Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel, and.
  • Vardi A; the Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel, and.
  • Futerman AH; the Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel, and.
  • Thiele C; the Department of Cell Biology of Lipids, LIMES Institute, University of Bonn, Bonn, Germany.
  • Wachten D; From the Minerva Max Planck Research Group, Molecular Physiology, and dagmar.wachten@caesar.de.
J Biol Chem ; 292(15): 6177-6189, 2017 04 14.
Article en En | MEDLINE | ID: mdl-28258214
The lysosomal acid ß-glucosidase GBA1 and the non-lysosomal ß-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 the GBA1 gene 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 ß-glucosidase activity in general.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esfingosina / Regulación hacia Abajo / Regulación Enzimológica de la Expresión Génica / Beta-Glucosidasa / Enfermedad de Gaucher / Modelos Biológicos Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: J Biol Chem Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esfingosina / Regulación hacia Abajo / Regulación Enzimológica de la Expresión Génica / Beta-Glucosidasa / Enfermedad de Gaucher / Modelos Biológicos Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: J Biol Chem Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos