Identification of a feedback loop involving beta-glucosidase 2 and its product sphingosine sheds light on the molecular mechanisms in Gaucher disease
| Autor: | Anthony H. Futerman, Britta Brügger, Heinz G. Körschen, Katharina Gutbrod, Dagmar Wachten, Per Haberkant, Peter Dörmann, Mathias J. Gerl, Ayelet Vardi, Anke Penno, Andreas Rennhack, Bernadette Breiden, Konrad Sandhoff, Sophie Schonauer, Christoph Thiele, Hila Zigdon, Diana N. Raju |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Ceramide congenital hereditary and neonatal diseases and abnormalities Metabolite Down-Regulation Biology Glucosylceramides Models Biological Biochemistry Gene Expression Regulation Enzymologic Cell Line Mice 03 medical and health sciences chemistry.chemical_compound Sphingosine Animals Humans Cytotoxic T cell Cytotoxicity Molecular Biology Cellular compartment Gaucher Disease beta-Glucosidase nutritional and metabolic diseases Lipid metabolism Cell Biology Lipid signaling Lipids 030104 developmental biology chemistry Glucosylceramidase |
| Zdroj: | Journal of Biological Chemistry |
| Popis: | The lysosomal acid beta-glucosidase GBA1 and the non-lysosomal beta-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 feed-back 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 beta-glucosidase activity in general. |
| Databáze: | OpenAIRE |
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