Identification of the Non-lysosomal Glucosylceramidase as β-Glucosidase 2

Boot, Rolf G.; Verhoek, Marri; Donker‐Koopman, Wilma E.; Strijland, Anneke; Marle, J. van; Overkleeft, Hermen S.; Wennekes, Tom; Aerts, Johannes M. F. G.

doi:10.1074/jbc.m610544200

Cited by 167 publications

(192 citation statements)

References 28 publications

Supporting

Mentioning

178

Contrasting

Unclassified

Order By: Relevance

“…Additionally, we provide evidence for impairment of T-cell maturation and egress of mature thymocytes in advanced GD. This prompts us to determine whether dense Gaucher cell infiltration in the thymus, as described hitherto, as well as in human GD (39), leads to elevated local concentrations of LysoGL1 and of sphingosine, thereof, via the action of neutral glucocerebrosidase, GBA2 (40,41). In this scenario, the abolition of sphingosine-1-phosphate gradient could be envisioned to block lymphocyte egress from the thymus (42).…”

Section: Discussionmentioning

confidence: 94%

Gaucher disease geneGBAfunctions in immune regulation

Liu

Halene

Yang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Inherited deficiency of acid β-glucosidase (GCase) due to biallelic mutations in the GBA (glucosidase, β, acid) gene causes the classic manifestations of Gaucher disease (GD) involving the viscera, the skeleton, and the lungs. Clinical observations point to immune defects in GD beyond the accumulation of activated macrophages engorged with lysosomal glucosylceramide. Here, we show a plethora of immune cell aberrations in mice in which the GBA gene is deleted conditionally in hematopoietic stem cells (HSCs). The thymus exhibited the earliest and most striking alterations reminiscent of impaired T-cell maturation, aberrant B-cell recruitment, enhanced antigen presentation, and impaired egress of mature thymocytes. These changes correlated strongly with disease severity. In contrast to the profound defects in the thymus, there were only limited cellular defects in peripheral lymphoid organs, mainly restricted to mice with severe disease. The cellular changes in GCase deficiency were accompanied by elevated T-helper (Th)1 and Th2 cytokines that also tracked with disease severity. Finally, the proliferation of GCase-deficient HSCs was inhibited significantly by both GL1 and Lyso-GL1, suggesting that the “supply” of early thymic progenitors from bone marrow may, in fact, be reduced in GBA deficiency. The results not only point to a fundamental role for GBA in immune regulation but also suggest that GBA mutations in GD may cause widespread immune dysregulation through the accumulation of substrates.

show abstract

Section: Discussionmentioning

confidence: 94%

Gaucher disease geneGBAfunctions in immune regulation

Liu

Halene

Yang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…glucose and ceramide as well as the reverse reaction consisting in the transfer of glucose to different lipid substrates [20,21]. The location of the missense variant, the high the family all together point toward a functional relevance of the p.Gly683Arg missense change to the pathogenesis.…”

Section: Clinical Findingsmentioning

confidence: 99%

Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis

et al. 2013

View full text Add to dashboard Cite

spasticity associated with a variable combination of neurologic and extra-neurologic signs and symptoms. Among ability is a frequent subtype, often inherited as a recessive trait (ARHSP-TCC). Within this heterogeneous subgroup, Abstract Complicated hereditary spastic paraplegias associated with early-onset forms of ARHSP with and (HSP) are a heterogeneous group of HSP characterized by without TCC, CYP2U1/SPG56, DDHD2/SPG54 and GBA2/SPG46, in a large population of selected complicated HSP patients by using a combined approach of trathem, HSP with thin corpus callosum and intellectual disditional-based and amplicon-based high-throughput pooled-sequencing. Three families with mutations were identified, one for each of the genes analyzed. Novel SPG11 and SPG15 represent the most frequent subtypes.homozygous mutations were identified in CYP2U1 We analyzed the mutation frequency of three genes spectrum of clinical entities associated with GBA2 mutations. Overall, each of three genes analyzed shows a low mutation frequency in a general population of complicated HSP (\1 % for either CYP2U1 or DDHD2 and approximately 2 % for GBA2). These findings underline once again the genetic heterogeneity of ARHSP-TCC and the clinical overlap between complicated HSP and the recessive ataxia syndromes.Spastic paraparesis _ CYP2U1 _ DDHD2 _ GBA2

show abstract

“…The enzyme, sensitive to CBE, is exclusively present in the microvilli of intestinal epithelial cells and possibly functions as a kind of digestive enzyme. Very recently, two research groups reported an alternative pathway (8,9), the catabolism of GlcCer by ␤-glucosidase 2 (GBA2), which has been known as a bile acid ␤-glucosidase (10). The enzyme, relatively nonsensitive to CBE, seems to be a membranebound enzyme of the ER (8) or located at or close to the cell surface (9).…”

Section: Glucosylceramide (Glccer)mentioning

confidence: 99%

Klotho-related Protein Is a Novel Cytosolic Neutral β-Glycosylceramidase

Hayashi

Okino

Kakuta

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Using C6-NBD-glucosylceramide (GlcCer) as a substrate, we detected the activity of a conduritol B epoxide-insensitive neutral glycosylceramidase in cytosolic fractions of zebrafish embryos, mouse and rat brains, and human fibroblasts. The candidates for the enzyme were assigned to the Klotho (KL), whose family members share a ␤-glucosidase-like domain but whose natural substrates are unknown. Among this family, only the KL-related protein (KLrP) is capable of degrading C6-NBDGlcCer when expressed in CHOP cells, in which Myc-tagged KLrP was exclusively distributed in the cytosol. In addition, knockdown of the endogenous KLrP by small interfering RNA increased the cellular level of GlcCer. The purified recombinant KLrP hydrolyzed 4-methylumbelliferyl-glucose, C6-NBD-GlcCer, and authentic GlcCer at pH 6.0. The enzyme also hydrolyzed the corresponding galactosyl derivatives, but each k cat /K m was much lower than that for glucosyl derivatives. The x-ray structure of KLrP at 1.6 Å resolution revealed that KLrP is a (␤/␣) 8 TIM barrel, in which Glu 165 and Glu 373 at the carboxyl termini of ␤-strands 4 and 7 could function as an acid/base catalyst and nucleophile, respectively. The substrate-binding cleft of the enzyme was occupied with palmitic acid and oleic acid when the recombinant protein was crystallized in a complex with glucose. GlcCer was found to fit well the cleft of the crystal structure of KLrP. Collectively, KLrP was identified as a cytosolic neutral glycosylceramidase that could be involved in a novel nonlysosomal catabolic pathway of GlcCer.

show abstract

Identification of the Non-lysosomal Glucosylceramidase as β-Glucosidase 2

Cited by 167 publications

References 28 publications

Gaucher disease geneGBAfunctions in immune regulation

Gaucher disease geneGBAfunctions in immune regulation

Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis

Klotho-related Protein Is a Novel Cytosolic Neutral β-Glycosylceramidase

Contact Info

Product

Resources

About