TY - JOUR
T1 - Identification of a feedback loop involving β-glucosidase 2 and its product sphingosine sheds light on the molecular mechanisms in Gaucher disease
AU - Schonauer, Sophie
AU - Koerschen, Heinz G.
AU - Penno, Anke
AU - Rennhack, Andreas
AU - Breiden, Bernadette
AU - Sandhoff, Konrad
AU - Gutbrod, Katharina
AU - Dormann, Peter
AU - Raju, Diana N.
AU - Haberkant, Per
AU - Gerl, Mathias J.
AU - Bruegger, Britta
AU - Zigdon, Hila
AU - Vardi, Ayelet
AU - Futerman, Anthony H.
AU - Thiele, Christoph
AU - Wachten, Dagmar
N1 - Fritz Thyssen Foundation; Deutsche Forschungsgemeinschaft [SFB645, TRR83]; Excellence Cluster ImmunoSensation, Bonn
PY - 2017/4/14
Y1 - 2017/4/14
N2 - 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 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 β-glucosidase activity in general.
AB - 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 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 β-glucosidase activity in general.
UR - http://www.scopus.com/inward/record.url?scp=85018500116&partnerID=8YFLogxK
U2 - https://doi.org/10.1074/jbc.M116.762831
DO - https://doi.org/10.1074/jbc.M116.762831
M3 - مقالة
SN - 0021-9258
VL - 292
SP - 6177
EP - 6189
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 15
ER -