The Ganglioside GD3 as the Greek Goddess Hecate: Several Faces Turned Towards as Many Directions

Malisan, Florence; Testi, Roberto

doi:10.1080/15216540500167179

Cited by 27 publications

(24 citation statements)

References 40 publications

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“…In recent years, GD3 has emerged as a cell death effector because of its role in apoptosis signaling in different cellular types by inducing mitochondrial damage (34,35). However, GD3 has also been reported to be overexpressed in a variety of tumors, especially in melanomas, where GD3 promotes tyrosine phosphorylation of paxillin, thereby resulting in an increased cell growth and an increased invasion by adhesion signals via integrin (36,37).…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…4 and 5). Multifaceted bioactivities have been reported for GM3 and GD3, including regulation of senescence, apoptosis, proliferation, and migration (63,64). As a result, GNE-initiated changes in the production of these gangliosides have the potential to elicit wide-ranging changes in cellular physiology.…”

Section: Discussionmentioning

confidence: 99%

Roles for UDP-GlcNAc 2-Epimerase/ManNAc 6-Kinase outside of Sialic Acid Biosynthesis

Wang

Sun

et al. 2006

Journal of Biological Chemistry

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Roles for UDP-GlcNAc 2-epimerase/ManNAc 6-kinase (GNE) beyond controlling flux into the sialic acid biosynthetic pathway by converting UDP-GlcNAc to N-acetylmannosamine are described in this report. Overexpression of recombinant GNE in human embryonic kidney (HEK AD293) cells led to an increase in mRNA levels for ST3Gal5 (GM3 synthase) and ST8Sia1 (GD3 synthase) as well as the biosynthetic products of these sialyltransferases, the GM3 and GD3 gangliosides. Conversely, down-regulation of GNE by RNA interference methods had the opposite, but consistent, effect of lowering ST3Gal5 and ST8Sia1 mRNAs and reducing GM3 and GD3 levels. Control experiments ensured that GNE-mediated changes in sialyltransferase expression and ganglioside biosynthesis were not the result of altered flux through the sialic acid pathway. Interestingly, exogenous GM3 and GD3 also changed the expression of GNE and led to reduced ST3Gal5 and ST8Sia1 mRNA levels, demonstrating a reciprocating feedback mechanism where gangliosides regulate upstream biosynthetic enzymes. Cellular responses to the GNE-mediated changes in ST3Gal5 and ST8Sia1 expression and GM3 and GD3 levels were investigated next. Conditions that led to reduced ganglioside production (e.g. short hairpin RNA exposure) stimulated proliferation, whereas conditions that resulted in increased ganglioside levels (e.g. recombinant GNE and exogenous gangliosides) led to reduced proliferation with a concomitant increase in apoptosis. Finally, changes to BiP expression and ERK1/2 phosphorylation consistent with apoptosis and proliferation, respectively, were observed. These results provide examples of specific biochemical pathways, other than sialic acid metabolism, that are influenced by GNE.Sialic acids, 9-carbon amino-monosaccharides, are ubiquitously displayed on mammalian cell surfaces. These sugars modulate biological and pathological events ranging from development and immune function to tumor biology and the viral and bacterial infection of cells (1-3). Not surprisingly, factors that influence the biosynthesis of sialic acid-containing glycoconjugates are of great interest due to the ever growing list of cellular functions influenced by this sugar. The biochemical steps that control sialic acid production, outlined in Fig. 1, have been intensely investigated in recent years (4) with a particular focus given to the bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc 6-kinase (GNE).2 Whereas GNE is known to control flux into the sialic acid biosynthetic pathway through conversion of UDP-GlcNAc to ManNAc (5) and has been described as the key determinant in the surface display of sialoglycans (6), the biological activity of this protein and its impact in health and disease remain far from understood. In particular, accumulating evidence that healthy cells maintain higher levels of GNE than required for sialic acid production raises the possibility that GNE may be a "moonlighting" protein that serves multiple functions within a cell (7,8).The hypothesis that cells have "excess" GNE is based...

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“…Gangliosides are also found in subcellular organelles of glycosphingolipid metabolism (endosomes, endoplasmic reticulum, Golgi apparatus, lysosomes), plasma lipoproteins, and the milk fat globule membrane (13,50,60). Present in small amounts in the diet (61), dietary gangliosides are incorporated into tissues and exert potent effects on cellular functions (31,43). Depending on location, concentration, and form, individual gangliosides play important roles in recognition, attachment, and translocation of cells, microbes, and macromolecules across membranes and regulate cell signaling and protein function (2,17,22,27,33,50).…”

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confidence: 98%

Uptake and fate of ganglioside GD3 in human intestinal Caco-2 cells

Schnabl¹,

Larcelet²,

Thomson³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Ganglioside GD3 is a glycosphingolipid found in colostrum, developing tissues, and tumors and is known to regulate cell growth, differentiation, apoptosis, and inflammation. Feeding a GD3-enriched diet to rats increases GD3 in intestinal lipid rafts and blood. The mechanism, efficiency, and fate of ganglioside absorption by human enterocytes have not been investigated. A model to study GD3 uptake by human intestinal cells was developed to test the hypothesis that enterocyte GD3 uptake is time and concentration dependent, with uptake efficiency and fate influenced by route of delivery. Caco-2 cells were exposed to GD3 on the apical or basolateral membrane (BLM) side for 6, 24, and 48 h. GD3 uptake, retention, transfer, and metabolism was determined. GD3 uptake across the apical and BLM was time and concentration dependent and reached a plateau. GD3 uptake across the BLM was more efficient than apical delivery. Apical GD3 was metabolized with some cell retention and transfer, whereas basolateral GD3 was mostly metabolized. This study demonstrates efficient GD3 uptake by enterocytes and suggests that the route of delivery influences ganglioside uptake and fate.

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The Ganglioside GD3 as the Greek Goddess Hecate: Several Faces Turned Towards as Many Directions

Cited by 27 publications

References 40 publications

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

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

Roles for UDP-GlcNAc 2-Epimerase/ManNAc 6-Kinase outside of Sialic Acid Biosynthesis

Uptake and fate of ganglioside GD3 in human intestinal Caco-2 cells

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