Animal Glycosphingolipids as Membrane Attachment Sites for Bacteria

Karlsson, Karl‐Anders

doi:10.1146/annurev.bi.58.070189.001521

Cited by 678 publications

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“…For instance, this approach has been quite effective in studying the metabolic effects of gangliosides and related sphingolipid derivatives. Under appropriate conditions, these lipids can rapidly transfer from their micelles, insert themselves into cellular plasma membranes, and modulate a variety of important metabolic events including the binding of certain pericellular adhesion proteins [38][39], viruses, bacterial cells and their toxins [40] as well as regulate cellular differentiation and proliferation, epidermal growth factor receptor activity [39], and protein kinase C activity [41]. Of course, gangliosides are not the only lipid class whose metabolic effects have become better understood via spontaneous lipid transfer [42][43][44][45][46].…”

Section: Ii-a Value As An Experimental Toolmentioning

confidence: 99%

Spontaneous lipid transfer between organized lipid assemblies

Brown

1992

Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes

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Section: Ii-a Value As An Experimental Toolmentioning

confidence: 99%

Spontaneous lipid transfer between organized lipid assemblies

Brown

1992

Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes

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“…These results demonstrate that heterologous transgenic expression of a glycosyltransferase can result in the expression of both the transgene and its secondary gene products and that the structures of milk oligosaccharides can be remodeled depending on expression of the appropriate enzyme. Furthermore, these results suggest that the lactating mammary gland may be a unique biosynthetic reactor for the production of biologically active oligosaccharides and glycoconjugates.Despite the fact that animal oligosaccharides are important in many biological and pathological processes (Karlsson, 1989;Kornfeld, 1992; Drickamer and Taylor, 1993;McEver et al, 1995), little is known about the regulation of animal cell glycoconjugate biosynthesis. Biosynthesis is influenced by expression of appropriate glycosyltransferases, correct targeting of the enzymes to the Golgi apparatus, sugar nucleotide levels, competition between enzymes, residence time of glycoconjugates in intracellular compartments, acceptor specificity of the enzymes, and many other factors (Kornfeld and Kornfeld, 1985;Kobata and Takasaki, 1992;Cummings, 1992;Baenziger, 1994).…”

mentioning

confidence: 99%

“…Despite the fact that animal oligosaccharides are important in many biological and pathological processes (Karlsson, 1989;Kornfeld, 1992; Drickamer and Taylor, 1993;McEver et al, 1995), little is known about the regulation of animal cell glycoconjugate biosynthesis. Biosynthesis is influenced by expression of appropriate glycosyltransferases, correct targeting of the enzymes to the Golgi apparatus, sugar nucleotide levels, competition between enzymes, residence time of glycoconjugates in intracellular compartments, acceptor specificity of the enzymes, and many other factors (Kornfeld and Kornfeld, 1985;Kobata and Takasaki, 1992;Cummings, 1992;Baenziger, 1994).…”

mentioning

confidence: 99%

Remodeling of Mouse Milk Glycoconjugates by Transgenic Expression of a Human Glycosyltransferase

Prieto

Mukerji

Kelder

et al. 1995

Journal of Biological Chemistry

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The mammary gland is a unique biosynthetic tissue that produces a variety of species-specific glycoconjugates, but the factors regulating the production of specific glycoconjugates are not well understood. To explore the underlying regulation, a fusion gene containing a cDNA encoding the human ␣1,2-fucosyltransferase (␣1,2FT), which generates the H-blood group antigen, flanked by the murine whey acidic protein promoter and a polyadenylation signal, was introduced into mice. Milk samples from transgenic animals contained soluble forms of the ␣1,2FT, as revealed by Western blots of milk samples using an anti-␣1,2FT antiserum and by the demonstration of ␣1,2FT enzyme activity. Milk from transgenic animals also contained large quantities of 2 -fucosyllactose (Fuc␣1-2Gal␤1-4Glc) and modified glycoproteins containing the H-antigen, whereas milk from control animals lacked these glycoconjugates. Expression levels of 2 -fucosyllactose were high in most animals and represented 1 ⁄3 to nearly 1 ⁄2 of the total milk oligosaccharides. These results demonstrate that heterologous transgenic expression of a glycosyltransferase can result in the expression of both the transgene and its secondary gene products and that the structures of milk oligosaccharides can be remodeled depending on expression of the appropriate enzyme. Furthermore, these results suggest that the lactating mammary gland may be a unique biosynthetic reactor for the production of biologically active oligosaccharides and glycoconjugates.Despite the fact that animal oligosaccharides are important in many biological and pathological processes (Karlsson, 1989;Kornfeld, 1992; Drickamer and Taylor, 1993;McEver et al., 1995), little is known about the regulation of animal cell glycoconjugate biosynthesis. Biosynthesis is influenced by expression of appropriate glycosyltransferases, correct targeting of the enzymes to the Golgi apparatus, sugar nucleotide levels, competition between enzymes, residence time of glycoconjugates in intracellular compartments, acceptor specificity of the enzymes, and many other factors (Kornfeld and Kornfeld, 1985;Kobata and Takasaki, 1992;Cummings, 1992;Baenziger, 1994). Experimental modulation of these factors has been difficult. One approach that has proven somewhat successful in vitro is to attempt to alter oligosaccharide biosynthesis by genetic manipulation of glycosyltransferases (Lee et al., 1989;Smith et al., 1990;Lowe et al., 1990). This approach has so far been limited to cultured and immortalized cell lines and has been useful in producing neoglycoconjugates for biological studies .One major site for glycoconjugate biosynthesis in animals, and one that has been of enormous historical importance in the field of glycobiology, is the lactating mammary gland. Milk contains, in addition to lactose, numerous glycoproteins (Patton et al., 1990;Fiat and Jollès, 1989) and a variety of free oligosaccharides (Kobata et al., 1972). The structure and composition of the free oligosaccharides in milk differ between mammals, but the human lac...

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“…As components of cellular receptors for microbes and their toxins (Karlsson 1989), glycolipids are also of worldwide importance: cholera toxin, shiga toxin and the verotoxin of Escherichia coli-an important cause of renal failure and the haemolytic-uraemic syndrome-immediately come to mind (Brown et al 1991;Boyce et al 1995). Through the systematic genetic 'knockout' approach taken by Dr Proia, however, we learned of the involvement of complex gangliosides in interleukin 2 signalling in T cells and of the role of GM3 gangliosides in the modulation of insulin receptor activity (Proia 2003).…”

Section: Role Of Glycolipidsmentioning

confidence: 99%

Future perspectives for glycolipid research in medicine

Cox

2003

Phil. Trans. R. Soc. Lond. B

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Medical interest in glycolipids has been mainly directed to the rare and complex glycosphingolipid storage disorders that are principally caused by unitary deficiencies of lysosomal acid hydrolases. However, glycolipids are critical components of cell membranes and occur within newly described membrane domains known as lipid rafts. Glycolipids are components of important antigen systems and membrane receptors; they participate in intracellular signalling mechanisms and may be presented to the immune system in the context of the novel CD1 molecules present on T lymphocytes. A knowledge of their mechanism of action in the control of cell growth and survival as well as developmental pathways is likely to shed light on the pathogenesis of the glycosphingolipid storage disorders as well as the role of lipid second messengers in controlling cell mobility and in the mobilization of intracellular calcium stores (a biological role widely postulated particularly for the lysosphingolipid metabolite sphingosine 1-phosphate). Other sphingolipid metabolites such as ceramide 1-phosphate may be involved in apoptotic responses and in phagocytosis and synaptic vesicle formation. The extraordinary pharmaceutical success of enzymatic complementation for Gaucher's disease using macrophage-targeted human glucocerebrosidase has focused further commercial interest in other glycolipid storage diseases: the cost of targeted enzyme therapy and its failure to restore lysosomal enzymatic deficiencies in the brain has also stimulated interest in the concept of substrate reduction therapy using diffusible inhibitory molecules. Successful clinical trials of the iminosugar Nbutyldeoxynojirimycin in type 1 Gaucher's disease prove the principle of substrate reduction therapy and have attracted attention to this therapeutic method. They will also foster important further experiments into the use of glycolipid synthesis inhibitors for the severe neuronopathic glycosphingolipidoses, for which no definitive treatment is otherwise available. Future glycolipid research in medicine will be directed to experiments that shed light on the role of sphingolipids in signalling pathways, and in the comprehensive characterization and their secretory products in relation to the molecular pathogenesis of the storage disorders; experiments of use to improve the efficiency of complementing enzymatic delivery to the lysosomal compartment of storage cells are also needed. Further systematic screening for inhibitory compounds with specific actions in the pathways of glycosphingolipid biosynthesis will undoubtedly lead to clinical trials in the neuronopathic storage disorders and to wider applications in the fields of immunity and cancer biology.

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Animal Glycosphingolipids as Membrane Attachment Sites for Bacteria

Cited by 678 publications

References 0 publications

Spontaneous lipid transfer between organized lipid assemblies

Spontaneous lipid transfer between organized lipid assemblies

Remodeling of Mouse Milk Glycoconjugates by Transgenic Expression of a Human Glycosyltransferase

Future perspectives for glycolipid research in medicine

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