The fate and function of glycosphingolipid glucosylceramide

Meer, Gerrit van; Wolthoorn, Jasja; Degroote, Sophie

doi:10.1098/rstb.2003.1266

Cited by 62 publications

(54 citation statements)

References 36 publications

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“…Indeed, glycosphingolipids, most likely GlcCer, are required for the vesicular pathway from the Golgi complex to the melanosome (reviewed in Ref. 68 ). The proposed mechanism is that GlcCer on the cytosolic side of Golgi membrane is required for the formation of a functional protein coat and subsequent vesicle budding.…”

Section: Ceramide and Cell Cycle Progressionmentioning

confidence: 99%

Glucosylceramide synthesis inhibition affects cell cycle progression, membrane trafficking, and stage differentiation in Giardia lamblia

Štefanić

Spycher

Morf

et al. 2010

Journal of Lipid Research

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Ceramide, a central molecule in the sphingolipid biosynthesis, plays a critical role as second messenger in cellular signaling that regulates antiproliferative processes, including apoptosis, cell differentiation, and cell cycle arrest in different cell types. Levels of ceramide, a highly bioactive molecule, must be tightly controlled by diverse, coordinated mechanisms, including ceramide degradation, phosphorylation, or sphingolipid metabolism. Glucosylceramide synthase (GCS), also defi ned as ceramide glucosyltransferase (CGT), metabolizes ceramide to glucosylceramide (GlcCer), a glycosylated form of ceramide that does not have antiproliferative activity. GCS plays a crucial role in cell survival after apoptotic stimuli, Abstract Synthesis of glucosylceramide via glucosylceramide synthase (GCS) is a crucial event in higher eukaryotes, both for the production of complex glycosphingolipids and for regulating cellular levels of ceramide, a potent antiproliferative second messenger. In this study, we explored the dependence of the early branching eukaryote Giardia lamblia on GCS activity. Biochemical analyses revealed that the parasite has a GCS located in endoplasmic reticulum (ER) membranes that is active in proliferating and encysting trophozoites. Pharmacological inhibition of GCS induced aberrant cell division, characterized by arrest of cytokinesis, incomplete cleavage furrow formation, and consequent block of replication. Importantly, we showed that increased ceramide levels were responsible for the cytokinesis arrest. In addition, GCS inhibition resulted in prominent ultrastructural abnormalities, including accumulation of cytosolic vesicles, enlarged lysosomes, and clathrin disorganization. Moreover, anterograde traffi cking of the encystations-specifi c protein CWP1 was severely compromised and resulted in inhibition of stage differentiation. Our results reveal novel aspects of lipid metabolism in G. lamblia and specifically highlight the vital role of GCS in regulating cell cycle progression, membrane traffi cking events, and stage differentiation in this parasite. In addition, we identifi ed ceramide as a potent bioactive molecule, underscoring the universal conservation of ceramide signaling in eukaryotes. -Štefanić,

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Section: Ceramide and Cell Cycle Progressionmentioning

confidence: 99%

Glucosylceramide synthesis inhibition affects cell cycle progression, membrane trafficking, and stage differentiation in Giardia lamblia

Štefanić

Spycher

Morf

et al. 2010

Journal of Lipid Research

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“…These mechanisms may include some of those suggested for vesicular or intercompartmental glycosphingolipid transport (Holthuis et al 2001;van Meer et al 2003), the latter possibly involving defined roles for specific transport proteins (Metz and Radin 1980;Wong M et al 1984;Yamada and Sasaki 1982).…”

Section: Future Studiesmentioning

confidence: 99%

Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data

Elleder

2006

J of Inher Metab Disea

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SummaryGaucher disease (GD), deficiency of acid glucosylceramidase (GlcCer‐ase) is characterized by deficient degradation of beta‐glucosylceramide (GlcCer). It is well known that, in GD, the lysosomal accumulation of uncleaved GlcCer is limited to macrophages, which are gradually converted to storage cells with well known cytology—Gaucher cells (GCs). On the basis of previous studies of the disorder and of a comparison with other lysosomal enzymopathies affecting degradation of the GlcCer‐based glycosphingolipid series, it is hypothesized that in other cell types (i.e. non‐macrophage cells) the uncleaved GlcCer, in GlcCer‐ase deficiency, is transferred to other cell compartments, where it may be processed and even accumulated to various degrees. The consequence of the abnormal extralysosomal load may differ according to the cell type and compartment targeted and may be influenced by genetically determined factors, by a number of acquired conditions, including the current metabolic situation. The sequelae of the uncleaved GlcCer extralysosomal transfer may range from probably innocent or positive stimulatory, to the much more serious, in which it interferes with a variety of cell functions, and in extreme cases, can lead to cell death. This alternative processing of uncleaved GlcCer may help to explain tissue alterations seen in GD that have, so far, resisted explanation based simply on the presence of GCs. Paralysosomal alternative processing may thus go a long way towards filling a long‐standing gap in the understanding of the molecular pathology of the disorder. The impact of this alternative process will most likely be inversely proportional to the level of residual GlcCer‐ase activity. Lysosomal sequestration of GlcCer in these cells is either absent or in those exceptional cases where it does occur, it is exceptional and rudimentary. It is suggested that paralysosomal alternative processing of uncleaved GlcCer is the main target for enzyme replacement therapy. The mechanism responsible for GlcCer transfer remains to be elucidated. It may also help in explaining the so far unclear origin of glucosylsphingosine (GlcSph) and define the mutual relation between these two processes.

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“…1. Also, in contrast to complex GSLs, which have a luminal/extracellular orientation in cellular membranes, GlcCer is in part uniquely oriented in the cell, being located in the cytosolic leaflet of cellular membranes with its carbohydrate moiety extending into the cytosolic compartment (2)(3)(4). This is a consequence of the cellular topology of GSL biosynthesis.…”

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confidence: 99%

Accumulation of Glucosylceramide in Murine Testis, Caused by Inhibition of β-Glucosidase 2

Walden

Sandhoff

Chuang

et al. 2007

Journal of Biological Chemistry

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One of the hallmarks of male germ cell development is the formation of a specialized secretory organelle, the acrosome. This process can be pharmacologically disturbed in C57BL/6 mice, and thus infertility can be induced, by small molecular sugar-like compounds (alkylated imino sugars). Here the biochemical basis of this effect has been investigated. Our findings suggest that in vivo alkylated imino sugars primarily interact with the non-lysosomal glucosylceramidase. This enzyme cleaves glucosylceramide into glucose and ceramide, is sensitive to imino sugars in vitro, and has been characterized as ␤-glucosidase 2 (GBA2). Imino sugars raised the level of glucosylceramide in brain, spleen, and testis, in a dose-dependent fashion. In testis, multiple species of glucosylceramide were similarly elevated, those having long acyl chains (C16 -24), as well as those with very long polyunsaturated acyl chains (C28 -30:5). Both of these GlcCer species were also increased in the testes from GBA2-deficient mice. When considering that the very long polyunsaturated sphingolipids are restricted to germ cells, these results indicate that in the testis GBA2 is present in both somatic and germ cells. Furthermore, in all mouse strains tested imino sugar treatment caused a rise in testicular glucosylceramide, even in a number of strains, of which the males remain fertile after drug administration. Therefore, it appears that acrosome formation can be derailed by accumulation of glucosylceramide in an extralysosomal localization, and that the sensitivity of male germ cells to glucosylceramide is genetically determined.

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The fate and function of glycosphingolipid glucosylceramide

Cited by 62 publications

References 36 publications

Glucosylceramide synthesis inhibition affects cell cycle progression, membrane trafficking, and stage differentiation in Giardia lamblia

Glucosylceramide synthesis inhibition affects cell cycle progression, membrane trafficking, and stage differentiation in Giardia lamblia

Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data

Accumulation of Glucosylceramide in Murine Testis, Caused by Inhibition of β-Glucosidase 2

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