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Identification of a feedback loop involving ?-glucosidase 2 and its product sphingosine sheds light on the molecular mechanisms in Gaucher disease.

ABSTRACT: The lysosomal acid ?-glucosidase GBA1 and the non-lysosomal ?-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 ?-glucosidase activity in general.

SUBMITTER: Schonauer S

PROVIDER: S-EPMC5391749 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Identification of a feedback loop involving β-glucosidase 2 and its product sphingosine sheds light on the molecular mechanisms in Gaucher disease.

Schonauer Sophie S Körschen Heinz G HG Penno Anke A Rennhack Andreas A Breiden Bernadette B Sandhoff Konrad K Gutbrod Katharina K Dörmann Peter P Raju Diana N DN Haberkant Per P Gerl Mathias J MJ Brügger Britta B Zigdon Hila H Vardi Ayelet A Futerman Anthony H AH Thiele Christoph C Wachten Dagmar D

The Journal of biological chemistry 20170303 15

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 <i>GBA1</i> 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 ...[more]

PMID: 28258214

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Project description:miR828 in Arabidopsis triggers the cleavage of Trans-Acting SiRNA Gene 4 (TAS4) transcripts and production of small interfering RNAs (ta-siRNAs). One siRNA, TAS4-siRNA81(-), targets a set of MYB transcription factors including PAP1, PAP2, and MYB113 which regulate the anthocyanin biosynthesis pathway. Interestingly, miR828 also targets MYB113, suggesting a close relationship between these MYBs, miR828, and TAS4, but their evolutionary origins are unknown. We found that PAP1, PAP2, and TAS4 expression is induced specifically by exogenous treatment with sucrose and glucose in seedlings. The induction is attenuated in abscisic acid (ABA) pathway mutants, especially in abi3-1 and abi5-1 for PAP1 or PAP2, while no such effect is observed for TAS4. PAP1 is under regulation by TAS4, demonstrated by the accumulation of PAP1 transcripts and anthocyanin in ta-siRNA biogenesis pathway mutants. TAS4-siR81(-) expression is induced by physiological concentrations of Suc and Glc and in pap1-D, an activation-tagged line, indicating a feedback regulatory loop exists between PAP1 and TAS4. Bioinformatic analysis revealed MIR828 homologues in dicots and gymnosperms, but only in one basal monocot, whereas TAS4 is only found in dicots. Consistent with this observation, PAP1, PAP2, and MYB113 dicot paralogs show peptide and nucleotide footprints for the TAS4-siR81(-) binding site, providing evidence for purifying selection in contrast to monocots. Extended sequence similarities between MIR828, MYBs, and TAS4 support an inverted duplication model for the evolution of MIR828 from an ancestral gymnosperm MYB gene and subsequent formation of TAS4 by duplication of the miR828* arm. We obtained evidence by modified 5'-RACE for a MYB mRNA cleavage product guided by miR828 in Pinus resinosa. Taken together, our results suggest that regulation of anthocyanin biosynthesis by TAS4 and miR828 in higher plants is evolutionarily significant and consistent with the evolution of TAS4 since the dicot-monocot divergence.

Dataset Information

Identification of a feedback loop involving ?-glucosidase 2 and its product sphingosine sheds light on the molecular mechanisms in Gaucher disease.

Publications

Identification of a feedback loop involving β-glucosidase 2 and its product sphingosine sheds light on the molecular mechanisms in Gaucher disease.

Similar Datasets

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