Lipids regulate the hydrolysis of membrane bound glucosylceramide by lysosomal β-glucocerebrosidase.

Publisher: Elsevier Country of Publication: United States NLM ID: 0376606 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1539-7262 (Electronic) Linking ISSN: 00222275 NLM ISO Abbreviation: J Lipid Res Subsets: MEDLINE

Publication: 2021- : [New York] : Elsevier
Original Publication: Memphis, Lipid Research, inc.

Gaucher Disease/*metabolism ; Glucosylceramidase/*genetics ; Glucosylceramides/*metabolism ; Niemann-Pick Diseases/*metabolism; Cholesterol/metabolism ; Gaucher Disease/genetics ; Gaucher Disease/pathology ; Genetic Association Studies ; Glucosylceramidase/metabolism ; Humans ; Hydrolysis ; Lipid Metabolism/genetics ; Lysophospholipids/metabolism ; Lysosomes/enzymology ; Monoglycerides/metabolism ; Niemann-Pick Diseases/genetics ; Niemann-Pick Diseases/pathology ; Saposins/metabolism

Glucosylceramide (GlcCer) is the primary storage lipid in the lysosomes of Gaucher patients and a secondary one in Niemann-Pick disease types A, B, and C. The regulatory roles of lipids on the hydrolysis of membrane bound GlcCer by lysosomal β-glucocerebrosidase (GBA1) was probed using a detergent-free liposomal assay. The degradation rarely occurs at uncharged liposomal surfaces in the absence of saposin (Sap) C. However, anionic lipids stimulate GlcCer hydrolysis at low pH by up to 1,000-fold depending on the nature and position of the negative charges in their head groups while cationic lipids inhibit the degradation, thus showing the importance of electrostatic interactions between the polycationic GBA1 and the negatively charged vesicle surfaces at low pH. Ceramide, fatty acids, monoacylglycerol, and diacylglycerol also stimulate GlcCer hydrolysis while SM, sphingosine, and sphinganine play strong inhibitory roles, thereby explaining the secondary storage of GlcCer in Niemann-Pick diseases. Surprisingly, cholesterol stimulates GlcCer degradation in the presence of bis(monoacylglycero)phosphate (BMP). Sap C strongly stimulates GlcCer hydrolysis even in the absence of BMP and the regulatory roles of the intraendolysosomal lipids on its activity is discussed. Our data suggest that these strong modifiers of GlcCer hydrolysis affect the genotype-phenotype correlation in several cases of Gaucher patients independent of the types.
(Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)

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Keywords: Gaucher disease; acylglycerols; anionic phospholipids; cationic lipids; cholesterol; electrostatic interaction; fatty acids; lysophospholipids; sphingomyelin; sphingosine

0 (Glucosylceramides)
0 (Lysophospholipids)
0 (Monoglycerides)
0 (Saposins)
0 (bis(monoacylglyceryl)phosphate)
97C5T2UQ7J (Cholesterol)
EC 3.2.1.45 (Glucosylceramidase)

Date Created: 20170128 Date Completed: 20170828 Latest Revision: 20210217

20240829

PMC5335586

10.1194/jlr.M073510

28126847