Limits...
O-acetylation of GD3: an enigmatic modification regulating apoptosis?

Chen HY, Varki A - J. Exp. Med. (2002)

View Article: PubMed Central - PubMed

Affiliation: Glycobiology Research and Training Center, Department of Medicine and Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Glycosphingolipids (GSLs) are amphipathic molecules with a polar glycan chain as a head group and a hydrophobic sphingosine-containing ceramide tail, which is typically embedded in the outer leaflet of the plasma membrane... Gd3 is a ganglioside with two Sias linked to a lactosylceramide core common to many GSLs (see Fig. 1)... Such newly synthesized gangliosides are delivered to the outer leaflet of the plasma membrane and eventually turned over via endocytosis and lysosomal degradation (; see Fig. 1)... The biological specificity of Sias can be modulated by substitutions or modifications at the 1, 4, 5, 7, 8, or 9 positions... O-acetyl esters are most commonly found at the 9-carbon position... Addition of Gd3 to intact cells induced apoptosis, and addition to isolated mitochondria gave a loss of mitochondrial transmembrane potential, along with release of apoptogenic factors such as cytochrome c and caspase-9... Gangliosides structurally related to Gd3 did not exhibit these effects in most systems... Cells that either express Gd3 synthase endogenously or by transfection became apoptotic when the viral esterase was also present, and this correlated with a reduction in 9AcGd3... The authors conclude that by turning part of pro-apoptotic Gd3 into ‘harmless’ 9AcGd3, 9-O-acetylation acts as an effective antiapoptotic mechanism... Regardless, as Gd3 is synthesized within the lumen of the Golgi and is then embedded in the outer leaflet of the plasma membrane, either of the above delivery systems would cause Gd3 incorporation into the inner leaflet of the outer mitochondrial membrane (see Fig. 1)... In contrast, the experiments with isolated mitochondria involve added Gd3, which should be incorporated with its polar glycan head-group facing outward, in the cytosol-facing leaflet of the outer mitochondrial membrane (see Fig. 1)... Such complexes might then be flipped over by the previously well-known phospholipid transfer proteins... In addition to the mechanism of “flipping,” the immediate downstream effectors of Gd3 that induce the mitochondrial changes need to be elucidated... Cloning of the putative Gd3:9(7)O-acetyl transferase(s) and esterase(s) would also help in understanding the regulation of 9(7)-O-acetylation in relation to Gd3 expression in different cell types and within different subcellular compartments... Finally, what about the effects of the less common intermediate form 7AcGd3, which cannot be deacetylated by any known O-acetylesterase?

Show MeSH
Subcellular compartments potentially involved in the biosynthesis, trafficking, and turnover of GD3 and AcGD3 are shown. Complexities involving 7- versus 9-AcGD3, and the possible action of O-acetylesterases are omitted. Various pathways for GD3-induced apoptosis are indicated, especially in relation to the proposed production and translocation of GD3 to mitochondrial membranes. Some of the unresolved topological issues are emphasized. Topological issues regarding ASM are not shown. See text for further discussion.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2196069&req=5

fig1: Subcellular compartments potentially involved in the biosynthesis, trafficking, and turnover of GD3 and AcGD3 are shown. Complexities involving 7- versus 9-AcGD3, and the possible action of O-acetylesterases are omitted. Various pathways for GD3-induced apoptosis are indicated, especially in relation to the proposed production and translocation of GD3 to mitochondrial membranes. Some of the unresolved topological issues are emphasized. Topological issues regarding ASM are not shown. See text for further discussion.

Mentions: Gangliosides are GSLs with one or more sialic acid (Sia) residues. Gd3 is a ganglioside with two Sias linked to a lactosylceramide core common to many GSLs (see Fig. 1) . Sia is a generic name for members of a family of 9-carbon sugars typically found at the termini of glycan chains on vertebrate glycoproteins and glycolipids. Many endogenous or exogenous receptors recognize Sias, mediating or modulating processes such as cell adhesion, differentiation, signal transduction, pathogen invasion, or toxin action (for a review, see reference 7). The biosynthesis of Gd3 is traditionally thought to occur in the ER-Golgi pathway, by the sequential addition to ceramide of a glucose, a galactose and two Sia residues, each step being catalyzed by distinct glycosyltransferases (see Fig. 1). The last three of these enzymes have their active sites oriented toward the lumen of Golgi compartments. Such newly synthesized gangliosides are delivered to the outer leaflet of the plasma membrane and eventually turned over via endocytosis and lysosomal degradation (1; see Fig. 1).


O-acetylation of GD3: an enigmatic modification regulating apoptosis?

Chen HY, Varki A - J. Exp. Med. (2002)

Subcellular compartments potentially involved in the biosynthesis, trafficking, and turnover of GD3 and AcGD3 are shown. Complexities involving 7- versus 9-AcGD3, and the possible action of O-acetylesterases are omitted. Various pathways for GD3-induced apoptosis are indicated, especially in relation to the proposed production and translocation of GD3 to mitochondrial membranes. Some of the unresolved topological issues are emphasized. Topological issues regarding ASM are not shown. See text for further discussion.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196069&req=5

fig1: Subcellular compartments potentially involved in the biosynthesis, trafficking, and turnover of GD3 and AcGD3 are shown. Complexities involving 7- versus 9-AcGD3, and the possible action of O-acetylesterases are omitted. Various pathways for GD3-induced apoptosis are indicated, especially in relation to the proposed production and translocation of GD3 to mitochondrial membranes. Some of the unresolved topological issues are emphasized. Topological issues regarding ASM are not shown. See text for further discussion.
Mentions: Gangliosides are GSLs with one or more sialic acid (Sia) residues. Gd3 is a ganglioside with two Sias linked to a lactosylceramide core common to many GSLs (see Fig. 1) . Sia is a generic name for members of a family of 9-carbon sugars typically found at the termini of glycan chains on vertebrate glycoproteins and glycolipids. Many endogenous or exogenous receptors recognize Sias, mediating or modulating processes such as cell adhesion, differentiation, signal transduction, pathogen invasion, or toxin action (for a review, see reference 7). The biosynthesis of Gd3 is traditionally thought to occur in the ER-Golgi pathway, by the sequential addition to ceramide of a glucose, a galactose and two Sia residues, each step being catalyzed by distinct glycosyltransferases (see Fig. 1). The last three of these enzymes have their active sites oriented toward the lumen of Golgi compartments. Such newly synthesized gangliosides are delivered to the outer leaflet of the plasma membrane and eventually turned over via endocytosis and lysosomal degradation (1; see Fig. 1).

View Article: PubMed Central - PubMed

Affiliation: Glycobiology Research and Training Center, Department of Medicine and Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Glycosphingolipids (GSLs) are amphipathic molecules with a polar glycan chain as a head group and a hydrophobic sphingosine-containing ceramide tail, which is typically embedded in the outer leaflet of the plasma membrane... Gd3 is a ganglioside with two Sias linked to a lactosylceramide core common to many GSLs (see Fig. 1)... Such newly synthesized gangliosides are delivered to the outer leaflet of the plasma membrane and eventually turned over via endocytosis and lysosomal degradation (; see Fig. 1)... The biological specificity of Sias can be modulated by substitutions or modifications at the 1, 4, 5, 7, 8, or 9 positions... O-acetyl esters are most commonly found at the 9-carbon position... Addition of Gd3 to intact cells induced apoptosis, and addition to isolated mitochondria gave a loss of mitochondrial transmembrane potential, along with release of apoptogenic factors such as cytochrome c and caspase-9... Gangliosides structurally related to Gd3 did not exhibit these effects in most systems... Cells that either express Gd3 synthase endogenously or by transfection became apoptotic when the viral esterase was also present, and this correlated with a reduction in 9AcGd3... The authors conclude that by turning part of pro-apoptotic Gd3 into ‘harmless’ 9AcGd3, 9-O-acetylation acts as an effective antiapoptotic mechanism... Regardless, as Gd3 is synthesized within the lumen of the Golgi and is then embedded in the outer leaflet of the plasma membrane, either of the above delivery systems would cause Gd3 incorporation into the inner leaflet of the outer mitochondrial membrane (see Fig. 1)... In contrast, the experiments with isolated mitochondria involve added Gd3, which should be incorporated with its polar glycan head-group facing outward, in the cytosol-facing leaflet of the outer mitochondrial membrane (see Fig. 1)... Such complexes might then be flipped over by the previously well-known phospholipid transfer proteins... In addition to the mechanism of “flipping,” the immediate downstream effectors of Gd3 that induce the mitochondrial changes need to be elucidated... Cloning of the putative Gd3:9(7)O-acetyl transferase(s) and esterase(s) would also help in understanding the regulation of 9(7)-O-acetylation in relation to Gd3 expression in different cell types and within different subcellular compartments... Finally, what about the effects of the less common intermediate form 7AcGd3, which cannot be deacetylated by any known O-acetylesterase?

Show MeSH