Defects of glycosyltransferase activities in human fibroblasts of Pk and p blood group phenotypes.

Kijimoto-Ochiai, Shigeko; Naiki, Masaharu; Makita, Akira

doi:10.1073/pnas.74.12.5407

Cited by 39 publications

(12 citation statements)

References 19 publications

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“…These results are consistent with a recent report that Gb4 was induced in response to TNF-α in human umbilical vein endothelial cells (20). Gb4 is the most prominent neutral GSL in human erythrocytes (21) and is an essential structure of blood group P antigen (22). The physiological function of Gb4 in vivo has not been demonstrated, although it has been shown to be an adhesion molecule on epithelial cells for bacteria (23), cancer cells (24), and some toxins (25).…”

Section: Discussionsupporting

confidence: 82%

TLR4–MD-2 complex is negatively regulated by an endogenous ligand, globotetraosylceramide

Kondo¹,

Ikeda

Tokuda³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Although endogenous ligands for Toll-like receptor (TLR)4-myeloid differentiation factor 2 (MD2) have not been well-understood, we here report that a globo-series glycosphingolipid, globotetraosylceramide (Gb4), attenuates the toxicity of lipopolysaccharides (LPSs) by binding to TLR4-MD-2. Because α1,4-galactosyltransferase (A4galt)-deficient mice lacking globo-series glycosphingolipids showed higher sensitivity to LPS than wild-type mice, we examined mechanisms by which globo-series glycosphingolipids attenuate LPS toxicity. Cultured endothelial cells lacking A4galt showed higher expression of LPS-inducible genes upon LPS treatment. In turn, introduction of A4galt cDNA resulted in the neo expression of Gb4, leading to the reduced expression of LPS-inducible genes. Exogenous Gb4 induced similar effects. As a mechanism for the suppressive effects of Gb4 on LPS signals, specific binding of Gb4 to the LPS receptor TLR4-MD-2 was demonstrated by coprecipitation of Gb4 with recombinant MD-2 and by native PAGE. A docking model also supported these data. Taken together with colocalization of TLR4-MD-2 with Gb4 in lipid rafts after LPS stimulation, it was suggested that Gb4 competes with LPS for binding to TLR4-MD-2. Finally, administration of Gb4 significantly protected mice from LPS-elicited mortality. These results suggest that Gb4 is an endogenous ligand for TLR4-MD-2 and is capable of attenuating LPS toxicity, indicating the possibility for its therapeutic application in endotoxin shock.innate immunity | sepsis

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Section: Discussionsupporting

confidence: 82%

TLR4–MD-2 complex is negatively regulated by an endogenous ligand, globotetraosylceramide

Kondo¹,

Ikeda

Tokuda³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The membranes of Pf phenotype also accumulate trihexosyl ceramide and are lacking globoside but do contain the P1-active glycolipid [10,22]. It has also been demonstrated that fibroblasts of p and P$ phenotypes are lacking a-galactosyl and P-N-acetylgalactosaminyl transferase activities, respectively [23].…”

Section: Resultsmentioning

confidence: 99%

Release of Oligosaccharides from Human Erythrocyte Membranes of Different Blood-Group-P Phenotypes by Trifluoroacetolysis

Lundblad¹,

Svensson²,

Löw³

et al. 1980

Eur J Biochem

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Human erythrocyte membranes of different blood-group-P phenotypes have been degraded by trifluoroacct olysis at conditions that will effect transamidation. This degradation resulted in dissolution of the membranes with concomitant degradation of proteins. Oligosaccharide chains linked to proteins and ceramides were released as their pertrifluoroacetylated derivatives, which generally are stable towards further action of the reagent. 2-Acetamido-2-deoxy-sugar residues were converted into their corresponding 2-deoxy-2-trifluoroacetamido derivatives. The mixture of pertrifluoroacetylated oligosaccharides obtained was de-0-trifluoroacetylated and de-N-trifluoroacetylated, reduced, acetylated, permethylated and analyzed by gas-liquid chromatography/mass spectrometry. Membranes obtained from two individuals with phenotype B, p (known to contain an excess of lactosyl ceramide) gave almost identical results with lactose released as the main component. From AZB,Pf cell membranes small amounts of lactose were obtained but the trisaccharide Gal(al-4)Gal(~1-4)Glc was the major component found. This trisaccharide is most likely derived from the Pk antigen (trihexosyl ceramide). Membranes from a donor with the phenotype B,P1 yielded small amounts of both lactose and the Pk trisaccharide together with a larger quantity of the tetrasaccharide GalNAc(~l-3)Gal(al-4)Gal(/J1-4)Glc. The tetrasaccharide represents the carbohydrate portion of the P antigen (globoside). From all three types of membranes the B-specific trisaccharide Gal(a1-3)Gal I ( a 1 4 Fuc a;i\ obtained. This compound is probably derived from specific degradation of blood-group-B-active glycoproteins and/or glycolipids. In addition to the oligosaccharides mentioned above a large number of others were observed but in lower amounts.Recently a new reaction, trifluoroacetolysis, has been developed which will effect transamidation at conditions where most glycosides and reducing sugars are stable, being converted into their pertrifluoroacetylated derivatives [I -41. Using this reaction procedures for the isolation of 0-and N-glycosidically linked carbohydrate chains in glycoproteins have been developed [5-71. It has also been demonstrated that the glycosidic bond to the sphingosine moiety in glycolipids is cleaved specifically by trifluoroacetolysis [8].Cell surface carbohydrates exist in the form of monosaccharides and oligosaccharides linked either to proteins or lipids which are buried in the cell mem-

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“…Further studies later showed the P antigen to be globotetraosylceramide (Gb 4 Cer, globoside, GalNAc␤3Gal␣4Gal␤4-GlcCer), 1 the most abundant neutral glycolipid in the erythrocyte membrane (2) as well as in other mesodermally derived tissues (3,4). Later it was found that human fibroblasts with the P k phenotype were deficient in ␤-N-acetylgalactosaminyltransferase activity (5).…”

mentioning

confidence: 99%

Molecular Basis of the Globoside-deficient Pk Blood Group Phenotype

Hellberg

Poole

Olsson

2002

Journal of Biological Chemistry

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The biochemistry and molecular genetics underlying the related carbohydrate blood group antigens P, P k , and LKE in the GLOB collection and P1 in the P blood group system are complex and not fully understood. Individuals with the rare but clinically important erythrocyte phenotypes P 1 k and P 2 k lack the capability to synthesize P antigen identified as globoside, the cellular receptor for Parvo-B19 virus and some P-fimbriated Escherichia coli. As in the ABO system, naturally occurring antibodies, anti-P of the IgM and IgG class with hemolytic and cytotoxic capacity, are formed. To define the molecular basis of the P k phenotype we analyzed the full coding region of a candidate gene reported in 1998 as a member of the 3-␤-galactosyltransferase family but later shown to possess UDP-N-acetylgalactosamine:globotriaosylceramide 3-␤-N-acetylgalactosaminyltransferase or globoside synthase activity. Homozygosity for different nonsense mutations (C 202 3 T and 538insA) resulting in premature stop codons was found in blood samples from two individuals of the P 2 k phenotype. Two individuals with P 1 k and P 2 k phenotypes were homozygous for missense mutations causing amino acid substitutions (E266A or G271R) in a highly conserved region of the enzymatically active carboxyl-terminal domain in the transferase. We conclude that crucial mutations in the globoside synthase gene cause the P k phenotype.

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Defects of glycosyltransferase activities in human fibroblasts of Pk and p blood group phenotypes.

Cited by 39 publications

References 19 publications

TLR4–MD-2 complex is negatively regulated by an endogenous ligand, globotetraosylceramide

TLR4–MD-2 complex is negatively regulated by an endogenous ligand, globotetraosylceramide

Release of Oligosaccharides from Human Erythrocyte Membranes of Different Blood-Group-P Phenotypes by Trifluoroacetolysis

Molecular Basis of the Globoside-deficient Pk Blood Group Phenotype

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