Modulation of cell functions by glycosphingolipid metabolic remodeling in the plasma membrane

Prinetti, Alessandro; Chigorno, Vanna; Mauri, Laura; Loberto, Nicoletta; Sonnino, Sandro

doi:10.1111/j.1471-4159.2007.04714.x

Cited by 31 publications

(22 citation statements)

References 151 publications

(264 reference statements)

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“…Sial-T2ϩ Cells Sialylates GM3 Ganglioside Immobilized onto a Solid Surface-Many reports have described the significance of the regulation of the glycolipid metabolism at the plasma membrane (13,14,17,18). However, the possibility that ecto-Sial-T2 may catalyze the conversion of GM3, belonging to the surface of neighboring cells, to the ganglioside GD3 has not yet been described.…”

Section: Ecto-sial-t2 From Cho-k1mentioning

confidence: 99%

Trans-activity of Plasma Membrane-associated Ganglioside Sialyltransferase in Mammalian Cells

Vilcaes¹,

Demichelis²,

Daniotti³

2011

Journal of Biological Chemistry

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Gangliosides are acidic glycosphingolipids that contain sialic acid residues and are expressed in nearly all vertebrate cells. They are synthesized at the Golgi complex by a combination of glycosyltransferase activities followed by vesicular delivery to the plasma membrane, where they participate in a variety of physiological as well as pathological processes. Recently, a number of enzymes of ganglioside anabolism and catabolism have been shown to be associated with the plasma membrane. In particular, it was observed that CMP-NeuAc:GM3 sialyltransferase (Sial-T2) is able to sialylate GM3 at the plasma membrane (ciscatalytic activity). In this work, we demonstrated that plasma membrane-integrated ecto-Sial-T2 also displays a trans-catalytic activity at the cell surface of epithelial and melanoma cells. By using a highly sensitive enzyme-linked immunosorbent assay combined with confocal fluorescence microscopy, we observed that ecto-Sial-T2 was able to sialylate hydrophobically or covalently immobilized GM3 onto a solid surface. More interestingly, we observed that ecto-Sial-T2 was able to sialylate GM3 exposed on the membrane of neighboring cells by using both the exogenous and endogenous donor substrate (CMP-N-acetylneuraminic acid) available at the extracellular milieu. In addition, the trans-activity of ecto-Sial-T2 was considerably reduced when the expression of the acceptor substrate was inhibited by using a specific inhibitor of biosynthesis of glycolipids, indicating the lipidic nature of the acceptor. Our findings provide the first direct evidence that an ecto-sialyltransferase is able to trans-sialylate substrates exposed in the plasma membrane from mammalian cells, which represents a novel insight into the molecular events that regulate the local glycosphingolipid composition.Glycosphingolipids are amphipathic molecules consisting of a ceramide lipid moiety linked to a glycan chain of variable length and structure. Among these are found gangliosides, which are sialosylated glycosphingolipids mainly located in the outer layer of the plasma membrane of vertebrate cells (1, 2) and have been implicated in many physiological processes, including growth, differentiation, migration and apoptosis through modulating both cell signaling processes and cell-tocell and cell-to-matrix interactions (3-6). Furthermore, gangliosides have been associated with a wide range of pathological processes, being receptors for both viruses and antibodies (7,8).The biosynthesis of gangliosides is mainly carried out in the lumen of the Golgi cisternae by a complex system of membrane-bound glycolipid acceptors, nucleotide sugar donors, glycosyltransferases, and nucleotide sugar transporters (1, 9). These neosynthesized gangliosides move through the Golgi complex to the plasma membrane via the lumenal surface of transport vesicles (10 -12). It is very well documented that glycosphingolipid expression, including gangliosides, is mainly regulated at the transcriptional and posttranscriptional levels of glycolipid glycosyltransferases a...

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Section: Ecto-sial-t2 From Cho-k1mentioning

confidence: 99%

Trans-activity of Plasma Membrane-associated Ganglioside Sialyltransferase in Mammalian Cells

Vilcaes¹,

Demichelis²,

Daniotti³

2011

Journal of Biological Chemistry

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“…However, an additional level of regulation of glycosphingolipid expression has been recently suggested to occur at the plasma membrane level, with the existence being reported of a plasma membrane-associated sialidase, termed Neu3, which is able to trigger selective ganglioside desialylation in different cell types (17)(18)(19). Moreover, ␤-hexosaminidase (20), ␤-glucosidase, and ␤-galactosidase (21) activities have also been demonstrated at the cell surface, suggesting their role in the remodeling of the plasma membrane glycosphingolipids, thus contributing to modulate lipid composition and membrane organization, and consequently, different signaling processes (21,22).…”

mentioning

confidence: 99%

Neobiosynthesis of Glycosphingolipids by Plasma Membrane-associated Glycosyltransferases*

Crespo¹,

Demichelis²,

Daniotti

2010

Journal of Biological Chemistry

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Gangliosides, complex glycosphingolipids containing sialic acids, are synthesized in the endoplasmic reticulum and in the Golgi complex. These neobiosynthesized gangliosides move via vesicular transport to the plasma membrane, becoming components of the external leaflet. Gangliosides can undergo endocytosis followed by recycling to the cell surface or sorting to the Golgi complex or lysosomes for remodeling and catabolism. Recently, glycosphingolipid catabolic enzymes (glycohydrolases) have been found to be associated with the plasma membrane, where they display activity on the membrane components. In this work, we demonstrated that ecto-ganglioside glycosyltransferases may catalyze ganglioside synthesis outside the Golgi compartment, particularly at the cell surface. Specifically, we report the first direct evidence of expression and activity of CMP-NeuAc: GM3 sialyltransferase (Sial-T2) at the cell surface of epithelial and melanoma cells, with membrane-integrated ectoSial-T2 being able to sialylate endogenously synthesized GM3 ganglioside as well as exogenously incorporated substrate. Interestingly, we also showed that ecto-Sial-T2 was able to synthesize GD3 ganglioside at the cell surface using the endogenously synthesized cytidine monophospho-N-acetylneuraminic acid (CMP-NeuAc) available at the extracellular milieu. In addition, the expression of UDP-GalNAc:LacCer/GM3/ GD3 N-acetylgalactosaminyltransferase (GalNAc-T) was also detected at the cell surface of epithelial cells, whose catalytic activity was only observed after feeding the cells with exogenous GM3 substrate. Thus, the relative interplay between the plasma membrane-associated glycosyltransferase and glycohydrolase activities, even when acting on a common substrate, emerges as a potential level of regulation of the local glycosphingolipid composition in response to different external and internal stimuli.

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“…[210,211] GØn-isson and co-workers have developed pyrrolidines that mimic the sphingosine backbone (53)(54)(55)(56), with 55 proving to be a potent GCS inhibitor. [212] Finally, BlØriot and co-workers recently reported moderately active azepane-based inhibitors of GCS (57)(58)(59)(60). [213] …”

Section: Inhibitors Of Glucosylceramide Synthasementioning

confidence: 99%

“…[57] In addition, direct metabolic remodeling of glycosphingolipids at the plasma membrane may result in local formation of simpler glycosphingolipids from complex ones. [58] The occurrence of nonlysosomal glucosylceramidase activity has long been known, and was recently identified as b-glucosidase 2 (GBA2). [59][60][61] GBA2, a 105 kDa protein with a transmembrane region, has not yet been assigned to a specific family of glycosidases.…”

Section: Mammalian (Glyco)sphingolipid Catabolismmentioning

confidence: 99%

Glycosphingolipids—Nature, Function, and Pharmacological Modulation

et al. 2009

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The discovery of the glycosphingolipids is generally attributed to Johan L. W. Thudichum, who in 1884 published on the chemical composition of the brain. In his studies he isolated several compounds from ethanolic brain extracts which he coined cerebrosides. He subjected one of these, phrenosin (now known as galactosylceramide), to acid hydrolysis, and this produced three distinct components. One he identified as a fatty acid and another proved to be an isomer of D-glucose, which is now known as D-galactose. The third component, with an "alkaloidal nature", presented "many enigmas" to Thudichum, and therefore he named it sphingosine, after the mythological riddle of the Sphinx. Today, sphingolipids and their glycosidated derivatives are the subjects of intense study aimed at elucidating their role in the structural integrity of the cell membrane, their participation in recognition and signaling events, and in particular their involvement in pathological processes that are at the basis of human disease (for example, sphingolipidoses and diabetes type 2). This Review details some of the recent findings on the biosynthesis, function, and degradation of glycosphingolipids in man, with a focus on the glycosphingolipid glucosylceramide. Special attention is paid to the clinical relevance of compounds directed at interfering with the factors responsible for glycosphingolipid metabolism.

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Modulation of cell functions by glycosphingolipid metabolic remodeling in the plasma membrane

Cited by 31 publications

References 151 publications

Trans-activity of Plasma Membrane-associated Ganglioside Sialyltransferase in Mammalian Cells

Trans-activity of Plasma Membrane-associated Ganglioside Sialyltransferase in Mammalian Cells

Neobiosynthesis of Glycosphingolipids by Plasma Membrane-associated Glycosyltransferases*

Glycosphingolipids—Nature, Function, and Pharmacological Modulation

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