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PubMed2002

Understanding the stepwise synthesis of glycolipids.

Glycolipid expression is highly regulated during development and differeniation. The control relies mainly on transcriptional modulation of key glycosyltransferases acting at the branching points of the pathway of biosynthesis. Transferases are Golgi residents that depend on N-glycosylation and oligosaccharide processing for proper folding in the endoplasmic reticulum. The N-terminal domain bears information for their transport to the Golgi, retention in the organelle and differential concentration in sub-Golgi compartments. In the Golgi, some transferases associate forming functional multienzyme complexes. It is envisaged that the machinery for synthesis in the Golgi complex, and its dynamics, constitute a potential target for fine tuning of the control of glycolipid expression according to cell demands.

Animals↗
PubMed1999

Interaction of peptides and proteins with bacterial surface glycolipids: a comparison of glycosphingolipids and lipopolysaccharides.

The bacterial cell wall of Gram-negative bacteria consists, in addition to the cytoplasmic membrane, of another permeability barrier, the outer membrane. The lipid distribution between both sides of this membrane is strictly asymmetric. The outer leaflet is made up of glycolipids, usually lipopolysaccharides. In Sphingomonas spp glycosphingolipids were found to substitute for lipopolysaccharides. In this review, it is shown by an electrophysiological approach that glycosphingolipid can replace lipopolysaccharide with respect to its function as antigenic surface structure as well as to its contribution to the diffusion barrier properties of the outer membrane. This review is focused on: (i) the function of porins, as examples of transmembrane proteins, in the different glycolipid environments; (ii) the interaction of polymyxin B with the outer membrane, as an example of polycationic antibacterial peptides; and (iii) the activation of the human complement system by lipopolysaccharides and glycosphingolipids.

Journal Article↗
PubMed2001

Urokinase-catalysed cleavage of the urokinase receptor requires an intact glycolipid anchor.

Urokinase (uPA) has the striking ability to cleave its receptor, uPAR, thereby inactivating the binding potential of this molecule. Here we demonstrate that the glycosylphosphatidylinositol (GPI) anchor of uPAR, which is attached to the third domain, is an important determinant in governing this reaction, even though the actual cleavage occurs between the first and second domains. Purified full-length GPI-anchored uPAR (GPI-uPAR) proved much more susceptible to uPA-mediated cleavage than recombinant truncated soluble uPAR (suPAR), which lacks the glycolipid anchor. This was not a general difference in proteolytic susceptibility since GPI-uPAR and suPAR were cleaved with equal efficiency by plasmin. Since the amino acid sequences of GPI-uPAR and suPAR are identical except for the C-terminal truncation, the different cleavage patterns suggest that the two uPAR variants differ in the conformation or the flexibility of the linker region between domains 1 and 2. This was supported by the fact that an antibody to the peptide AVTYSRSRYLE, amino acids 84-94 in the linker region, recognizes GPI-uPAR but not suPAR. This difference in the linker region is thus caused by a difference in a remote hydrophobic region. In accordance with this model, when the hydrophobic lipid moiety was removed from the glycolipid anchor by phospholipase C, low concentrations of uPA could no longer cleave the modified GPI-uPAR and the reactivity to the peptide antibody was greatly decreased. Naturally occurring suPAR, purified from plasma, was found to have a similar resistance to uPA cleavage as phospholipase C-treated GPI-uPAR and recombinant suPAR.

Animals↗
PubMed1995

Biosynthesis of the glycolipid anchor of lipophosphoglycan and the structurally related glycoinositolphospholipids from Leishmania major.

The major macromolecule on the surface of the protozoan parasite Leishmania major is a lipophosphoglycan (LPG) which contains a glycosylphosphatidylinositol glycolipid anchor. This parasite also synthesizes a complex family of abundant low-molecular-mass glycoinositolphospholipids (GIPLs) which are structurally related to the LPG anchor. In this study, L. major promastigotes were metabolically labelled with [3H]GlcN, and the kinetics of incorporation into free glycolipids and the LPG anchor followed to elucidate the pathway of GIPL biosynthesis and possible precursor-product relationships between the GIPLs and LPG. Labelled GIPLs were identified by TLC and by liquid chromatography of the released headgroups, before and after enzymic and chemical cleavage. On the basis of the measured specific radioactivities of the GIPLs, and their kinetics of radiolabelling, we suggest the pathway GlcN-PI-->Man1GlcN-PI (M1)-->Man2GlcN-PI (iM2)-->GalfMan2GlcN-PI (GIPL-1)-->Gal1GalfMan2GlcN-PI (GIPL-2)-->Gal2GalfMan2GlcN-PI (GIPL-3). All of the GIPLs were shown to contain alkylacylglycerol or lyso-alkylglycerol lipid moieties with the exception of the earliest intermediate, glucosaminylphosphatidylinositol (GlcN-PI), which contained both alkylacylglycerol and diacylglycerol. A significant proportion (approx. 50%) of GIPL-3 appeared to be selectively modified by the addition of a Glc-1-PO4 residue to one of the mannose residues (P-GIPL-3). On the basis of the specific radioactivity and kinetics of labelling of GIPL-3 and P-GIPL-3 we suggest that both of these low-abundance species are rapidly utilized as LPG precursors. The turnover of LPG and the GIPLs was also studied by [3H]Gal pulse-chase labelling and cell-surface labelling experiments. Whereas LPG was rapidly shed from the cell surface, consistent with previous studies, the GIPLs (both the total cellular and cell-surface pools) had a much slower turnover. These results suggest that the majority of the GIPLs do not act as LPG precursors and indicate that the cellular levels of these molecules is determined, at least in part, by the rate at which they are shed from the cell surface.

Animals↗
PubMed1979

Differential activities of glycolipid glycosyltransferases in Tay-Sachs disease: studies in cultured cells from cerebrum.

Four different glycolipid:glycosyltransferase activities involved in the biosynthesis in vitro of gangliosides and blood group-related glycosphingolipids have been tested in a simian virus 40-transformed glial cell culture derived from the cerebrum of a fetus with Tay-Sachs disease (TSD). The TSD cultured brain cells contained little activity of either UDP-Gal:GM2(beta 1-3)galactosyltransferase (GalT-3; EC 2.4.1.62), which catalyzes the formation of GM1a from GM2 (tay-Sachs) ganglioside, or GDP-Fuc:nLcOse4Cer (alpha 1-2)fucosyltransferase (FucT-2; EC 2.4.1.89), which catalyzes the formation of H1 glycolipid from nLcOse4Cer. These cells contained a potent inhibitor of the second reaction (catalyzed by a Golgi-rich membrane fraction from bovine spleen), whereas no inhibition of the first reaction (catalyzed by a membrane fraction from 14-day-old embryonic chicken brain) was observed. The activity of UDP-Gal:LcOse3Cer(beta 1-4)galactosyltransferase (GalT-4; EC 2.4.1.86) was 30- to 80-fold higher than the activity of GalT-3. The presence of CMP-AcNeu:nLcOse4Cer sialyltransferase activity and the absence of either GalT-3 or FucT-2 suggested a probable pathway for the synthesis of sialylneolactotetraosylceramide [GM1b(GlcNAc)] in addition to a specific blockage of GM1a ganglioside synthesis from GM2 in these TSD transformed cells.

ABO Blood-Group System↗
PubMed2000

Cloning and expression of glycolipid transfer protein from bovine and porcine brain.

Glycolipid transfer protein (GLTP) is a small (23-24 kDa), basic protein (pI congruent with 9.0) that accelerates the intermembrane transfer of various glycolipids. Here, we report the first cloning of cDNAs that encode the bovine and porcine GLTPs. The cDNA open reading frame for bovine GLTP was constructed by bridge-overlapping extension polymerase chain reaction (PCR) after obtaining partial coding cDNA clones by hot start, seminested, and rapid amplification of cDNA ends-PCR. The cDNA open reading frame for porcine GLTP was constructed by reverse transcriptase-PCR. The encoded amino acid sequences in the full-length bovine and porcine cDNAs were identical, consisting of 209 amino acid residues, and were nearly the same as the published sequence determined by Edman degradation. The cDNA encoded one additional amino acid at the N terminus (methionine), arginine at positions 10 and 200 instead of lysine, and threonine at position 65 instead of alanine. Expression of GLTP-cDNA in Escherichia coli using pGEX-6P-1 vector resulted in glutathione S-transferase (GST)-GLTP fusion protein. Regulation of growth and induction conditions led to approximately 50% of expressed fusion protein being soluble and active. Proteolytic cleavage of GST-GLTP fusion protein (bound to GST-Sepharose) and affinity purification resulted in fully active GLTP. Northern blot analyses of bovine tissues showed a single transcript of approximately 2.2 kilobases and the following hierarchy of mRNA levels: cerebrum > kidney > spleen congruent with lung congruent with cerebellum > liver > heart muscle. Reverse transcriptase-PCR analyses of mRNA levels supported the Northern blot results.

Amino Acid Sequence↗
PubMed2006

Inactivation of Corynebacterium glutamicum NCgl0452 and the role of MgtA in the biosynthesis of a novel mannosylated glycolipid involved in lipomannan biosynthesis.

Mycobacterium tuberculosis PimB has been demonstrated to catalyze the addition of a mannose residue from GDP-mannose to a monoacylated phosphatidyl-myo-inositol mannoside (Ac(1)PIM(1)) to generate Ac(1)PIM(2). Herein, we describe the disruption of its probable orthologue Cg-pimB and the chemical analysis of glycolipids and lipoglycans isolated from wild type Corynebacterium glutamicum and the C. glutamicum::pimB mutant. Following a careful analysis, two related glycolipids, Gl-A and Gl-X, were found in the parent strain, but Gl-X was absent from the mutant. The biosynthesis of Gl-X was restored in the mutant by complementation with either Cg-pimB or Mt-pimB. Subsequent chemical analyses established Gl-X as 1,2-di-O-C(16)/C(18:1)-(alpha-d-mannopyranosyl)-(1-->4)-(alpha-d-glucopyranosyluronic acid)-(1-->3)-glycerol (ManGlcAGroAc(2)) and Gl-A as the precursor, GlcAGroAc(2). In addition, C. glutamicum::pimB was still able to produce Ac(1)PIM(2), suggesting that Cg-PimB catalyzes the synthesis of ManGlcAGroAc(2) from GlcAGroAc(2). Isolation of lipoglycans from C. glutamicum led to the identification of two related lipoglycans. The larger lipoglycan possessed a lipoarabinomannan-like structure, whereas the smaller lipoglycan was similar to lipomannan (LM). The absence of ManGlcA-GroAc(2) in C. glutamicum::pimB led to a severe reduction in LM. These results suggested that ManGlcAGroAc(2) was further extended to an LM-like molecule. Complementation of C. glutamicum::pimB with Cg-pimB and Mt-pimB led to the restoration of LM biosynthesis. As a result, Cg-PimB, which we have assigned as MgtA, is now clearly defined as a GDP-mannose-dependent alpha-mannosyltransferase from our in vitro analyses and is involved in the biosynthesis of ManGlcAGroAc(2).

Adenosine Triphosphatases↗
PubMed1990

Glycolipids and transmembrane signaling: antibodies to galactocerebroside cause an influx of calcium in oligodendrocytes.

This is the first study to provide evidence that one function for the surface glycolipid galactocerebroside (GalC) is participation in the opening of Ca2+ channels in oligodendroglia in culture. This glycolipid is a unique differentiation marker for myelin-producing cells; antibodies to GalC have been shown to markedly alter oligodendroglial morphology via disruption of microtubules (Dyer, C. A., and J. A. Benjamins. 1988. J. Neurosci. 8:4307-4318). This study demonstrates that extracellular EGTA blocks anti-GalC-induced disassembly of microtubules in oligodendroglial membrane sheets, demonstrating that an influx of extracellular Ca2+ mediates the cytoskeletal changes. The Ca2+ influx was examined directly by loading oligodendroglia with the fluorescent dye Indo-1 in defined medium, and measuring changes in Ca2+ in individual cells with a laser cytometer. Upon addition of anti-GalC IgG, a marked sustained increase in intracellular Ca2+ occurred in 80% of the oligodendroglia observed. EGTA blocked the increase, indicating the increase is due to an influx of extracellular Ca2+, and not due to release from intracellular stores. The effect is specific, since Ca2+ levels remain normal in oligodendroglia treated with nonimmune IgG; astrocytes do not respond to the anti-GalC. The Ca2+ response in oligodendrocytes is dependent on concentration of antibody and GalC on the oligodendroglial membrane surface. The Ca2+ influx is not mediated by voltage-sensitive Ca2+ channels: it is not blocked by cadmium, and depolarization with K+ does not mimic the response. The kinetics of the response suggest that second messenger-mediated opening of Ca2+ channels is involved.

Animals↗
PubMed1993

Glucose induces lipolytic cleavage of a glycolipidic plasma membrane anchor in yeast.

In the yeast Saccharomyces cerevisiae an amphiphilic cAMP-binding protein has been found recently to be anchored to plasma membranes by virtue of a glycolipid structure (Müller and Bandlow, 1991a, 1992). The cAMP-binding parameters of this protein are affected by the lipolytic removal of the glycosylphosphatidylinositol (GPI) membrane anchor by exogenous (G)PI-specific phospholipases C or D (PLC or PLD) (Müller and Bandlow, 1993) suggesting a regulatory role of glycolipidic membrane anchorage. Here we report that transfer of yeast cells from lactate to glucose medium results in the conversion of the amphiphilic form of the cAMP receptor protein into a hydrophilic version accompanied by the rapid loss of fatty acids from the GPI anchor of the [14C]palmitic acid-labeled protein. Analysis of the cleavage site identifies [14C]inositol phosphate as the major product after treatment of the soluble, [14C]inositol-labeled protein with nitrous acid which destroys the glucosamine constituent of the anchor. Together with the observed cross-reactivity of the hydrophilic fragment with antibodies directed against the cross-reacting determinant of soluble trypanosomal variable surface glycoproteins (i.e., myo-inositol-1,2-cyclic phosphate) this demonstrates that, in membrane release, the initial cleavage event is catalyzed by an intrinsic GPI-PLC activated upon transfer of cells to glucose medium. Release from the plasma membrane in soluble form requires, in addition, the presence of high salt or alpha-methyl mannopyranoside, or the removal of the carbohydrate moieties, because otherwise the protein remains associated with the membrane presumably at least in part via its N-glycosidic carbohydrate side chains. The data point to the possibility that cleavage of the anchor could play a role in the transfer of the signal for the nutritional situation to the interior of the cell.

Carrier Proteins↗
PubMed1996

Endocytosis of GPI-anchored proteins in human lymphocytes: role of glycolipid-based domains, actin cytoskeleton, and protein kinases.

GPI-anchored surface proteins mediate many important functions, including transport, signal transduction, adhesion, and protection against complement. They cluster into glycolipid-based membrane domains and caveolae, plasmalemmal vesicles involved in the transcytosis and endocytosis of these surface proteins. However, in lymphocytes, neither the characteristic flask shaped caveolae nor caveolin, a transmembrane protein typical of caveolae, have been observed. Here, we show that the GPI-anchored CD59 molecule on Jurkat T cells is internalized after cross-linking, a process inhibited by nystatin, a sterol chelating agent. Clustered CD59 molecules mostly accumulate in non-coated invaginations of the lymphocyte membrane before endocytosis, in marked contrast with the pattern of CD3-TCR internalization. Cytochalasin H blocked CD59 internalization in lymphocytes, but neither CD3 internalization nor transferrin uptake. Confocal microscopy analysis of F-actin distribution within lymphocytes showed that CD59 clusters were associated with patches of polymerized actin. Also, we found that internalization of CD59 was prevented by the protein kinase C inhibitor staurosporine and by the protein kinase A activator forskolin. Thus, in lymphocytes, as in other cell types, glycolipid-based domains provide sites of integration of signaling pathways involved in GPI-anchored protein endocytosis. This process, which is regulated by both protein kinase C and A activity, is tightly controlled by the dynamic organization of actin cytoskeleton, and may be critical for polarized contacts of circulating cells.

Actins↗
PubMed2002

Presentation of the same glycolipid by different CD1 molecules.

Five CD1 molecules are expressed in humans and it is unclear whether they have specialized or redundant functions. We found that sulfatide is a promiscuous CD1-binding ligand and have isolated T cell clones that are specific for sulfatide and restricted by distinct CD1 molecules. These clones have been used to compare the capacity of different CD1 to present the same glycolipid, to induce effector functions, and to form persistent immunogenic complexes. CD1a, CD1b, and CD1c molecules similarly load sulfatide on the cell surface without processing, and prime Th1 and Th2 responses. Stimulation by sulfatide-loaded CD1a persists much longer than that by CD1b and CD1c in living cells. Use of recombinant soluble CD1a confirmed the prolonged capacity to stimulate T cells. Moreover, other glycosphingolipids bind to all CD1, which suggests the presence of additional promiscuous ligands. Thus, group I CD1 molecules present an overlapping set of self-glycolipids, even though they are quite divergent from an evolutionary point of view.

Antigen Presentation↗
PubMed2005

Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule.

Mycobacterium tuberculosis (Mtb) infection remains a global health crisis. Recent genetic evidence implicates specific cell envelope lipids in Mtb pathogenesis, but it is unclear whether these cell envelope compounds affect pathogenesis through a structural role in the cell wall or as pathogenesis effectors that interact directly with host cells. Here we show that cyclopropane modification of the Mtb cell envelope glycolipid trehalose dimycolate (TDM) is critical for Mtb growth during the first week of infection in mice. In addition, TDM modification by the cyclopropane synthase pcaA was both necessary and sufficient for proinflammatory activation of macrophages during early infection. Purified TDM isolated from a cyclopropane-deficient pcaA mutant was hypoinflammatory for macrophages and induced less severe granulomatous inflammation in mice, demonstrating that the fine structure of this glycolipid was critical to its proinflammatory activity. These results established the fine structure of lipids contained in the Mtb cell envelope as direct effectors of pathogenesis and identified temporal control of host immune activation through cyclopropane modification of TDM as a critical pathogenic strategy of Mtb.

Animals↗
PubMed1988

Production and characterization of a mouse monoclonal antibody to the glycolipid asialo-GM1.

The glycosphingolipid asialo-GM1 (aGM1) is a true differentiation antigen of murine lymphoid cells. This glycolipid is highly immunogenic in the rabbit, but the antisera produced shows some cross reactivity with GM1, the naturally occurring sialylated derivative of aGM1. In the present study we examined the ability to raise anti-aGM1 antisera in the mouse. We compared the efficiency of several immunization methods in various strains of mice. The most effective procedure involved repeated intraperitoneal injections of aGM1-cholesterol rich particles in the NZB mouse. Hybrid B cell lines were generated by fusion of mouse myeloma cells with the splenocytes of an NZB mouse immunized with aGM1. The specificity of the antisera produced and of the monoclonal antibody secreted by one of these hybridomas (103HT30) was defined by ELISA and by immunostaining on thin layer chromatograms. The monoclonal antibody 103HT30 is an IgM. It reacted with aGM1 but not with any of the structurally-related ganglioside or neutral glycolipids tested. In particular, 103HT30 monoclonal antibody did not present any detectable cross-reactivity with GM1.

Animals↗
PubMedDate not supplied

Lipooligosaccharides: the principal glycolipids of the neisserial outer membrane.

The outer-membrane glycolipids of bacteria that colonize mucosal surfaces that are not routinely bathed by bile acids often lack the long, hydrophilic and neutral polysaccharides that protect the lipid membranes of enteric bacteria from dispersal. The glycolipid from these organisms is properly termed a lipooligosaccharide. A Neisseria strain makes from two to six lipooligosaccharide molecules that range in Mr from 3,150 to 7,100. Different species of Neisseria commonly make lipooligosaccharides of identical Mr and epitope content. Differences in oligosaccharides account for most of the observed physical heterogeneity. Oligosaccharides consist of (1) partially conserved and highly substituted basal oligosaccharides that branch at heptose residues; (2) a linear segment consisting of (hexose)n residues that determines the length of the oligosaccharide; and (3) terminal sequences that are similar to those of glycosphingolipids. Epitope expression is linked to physical heterogeneity and is modified by the molecular environment of the outer membrane. Serotype epitopes are present only on lipooligosaccharides of a certain Mr. Certain lipooligosaccharides regulate complement activation onto the bacterial surface and, hence, immune lysis.

Animals↗
PubMed1988

Pathogenesis of shigella diarrhea: evidence for a developmentally regulated glycolipid receptor for shigella toxin involved in the fluid secretory response of rabbit small intestine.

Shigella toxin reproduces the major manifestations of shigellosis in ligated intestinal loops from adult rabbits and binds to a microvillus membrane (MVM) glycolipid receptor, globotriaosylceramide (Gb3). Because neonatal human shigellosis is uncommon, we used the animal model for obtaining MVMs from rabbits of different ages to determine the presence of toxin receptors and Gb3 and to measure the fluid secretory response to toxin in ligated ileal loops. A single class of MVM receptors for 125I-labeled shigella toxin, first detected at 20 d of age, reached adult levels by 24 d (n = 1.7-23.8 X 10(10)/micrograms of protein; K = 1.1-3.8 X 10(9) M-1). Binding was specific for toxin subunit B. A toxin binding MVM glycolipid, identified as Gb3, was detected in animals greater than or equal to 16 d of age by high-performance thin-layer chromatography and autoradiography. Fluid secretion in response to shigella toxin in ligated small bowel loops occurred in temporal relation to the appearance of Gb3, a result thus indicating the involvement of Gb3 in mediating the toxin effects.

Aging↗
PubMed1978

Preparation and properties of antisera to glycolipid of guinea pig erythrocyte membrane.

Antibodies against a glycolipid of guinea pig erythrocyte membranes were prepared in rabbits by immunization with guinea pig erythrocyte stroma or the purified glycolipid, gangliotriaosylceramide. The antibodies agglutinated guinea pig erythrocytes. The specificity of antibodies could be revealed by several immunochemical methods, including inhibition of hemagglutination, immunodiffusion, agglutination of liposomes, and complement fixation. The antibodies were specific for gangliotriaosylceramide.

Animals↗
PubMed1987

Antibody to endotoxin core glycolipid reverses reticuloendothelial system depression in an animal model of severe sepsis and surgical injury.

To study the effect of severe sepsis on the function of the reticuloendothelial system (RES) we have measured the clearance kinetics and organ distribution of both low-dose technetium tin colloid (TTC) and 75selenomethionine-labelled E. coli in rabbits 24 hours after either sham laparotomy or appendix devascularization. Sepsis resulted in similar delayed blood clearance and reduced liver (Kupffer cell) uptake of both TTC and E. coli. To investigate the ability of polyclonal antibody to E. coli-J-5 (core glycolipid) to improve RES function in the same model of sepsis, further animals were pretreated with either core glycolipid antibody or control serum (10 ml IV) 2 hours before induction of sepsis. TTC clearance kinetics were determined 24 hours later. Antibody pretreated animals showed: a reduced incidence of bacteremia; normalization of the rate of blood clearance and liver uptake of TTC; and a 'rebound' increase in splenic uptake of TTC. We conclude that antibody to E. coli-J-5 enhances bacterial clearance by the RES.

Animals↗
PubMed1970

Effect of Growth Temperature on the Lipid Composition of Cyanidium caldarium: II. Glycolipid and Phospholipid Components.

Cyanidium caldarium was grown at 20 and 55 C and harvested during exponential growth phase. Lipids were extracted and separated by silicic acid column and thin layer chromatography. The major glycolipids were identified as mono- and digalactosyl diglyceride and sulfolipid. Major phospholipids were identified as phosphatidyl choline and phosphatidyl ethanolamine. The cells grown at 20 C contained significantly larger quantities of these glycolipids and phospholipids than cells grown at 55 C.Fatty acid analysis showed that in all cases the cells grown at 20 C contained more unsaturated fatty acids than the cells grown at 55 C. Cells grown at 55 C were shown to lack linolenic acid, in contrast to cells grown at 20 C, which contained appreciable quantities in certain lipid components. For example, monogalactosyl diglyceride had 57% of its fatty acids in the form of linolenic acid. Cells grown at 55 C were 10 to 15 C more stable to disruption by heating than cells grown at 20 C. The greater thermostability of the latter was attributed to a higher degree of saturation of their membrane fatty acids.

Journal Article↗