Verotoxin Receptor Glycolipid in Human Renal Tissue

Boyd, Beth; Lingwood, Clifford A.

doi:10.1159/000185286

Cited by 196 publications

(123 citation statements)

References 5 publications

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“…Because mutant mice were observed to be perfect negative controls in immunohistochemistry, it was possible to distinguish minimal expression of Gb3/CD77 from the background and confirm that the main targets of VTs in tissue damage were Gb3/CD77 on endothelial cells in restricted regions (10,25). There have been numerous studies on the expression of Gb3/CD77 in human (16,(25)(26)(27)(28) and mouse (17,18) tissues, with some ambiguity observed in the precise localization thereof.…”

Section: Discussionmentioning

confidence: 94%

“…However, the effects of LPS on VT toxicity depend on when it is administered (31). In addition, the mouse strains used and tissue origins of endothelial cells are also critical for the assessment of LPS effects (10,31). In our results, the ␣1,4Gal-T gene might be induced by LPS via cytokine induction, but it scarcely affected the sensitivity to VTs.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, tissue damage by VTs is considered to depend on Gb3 expression in individual tissues (10). However, the following issues remain to be clarified, specifically, whether Gb3 is the only specific receptor for VTs in vivo and whether clinical signs of HUS are dependent upon Gb3 expression.…”

mentioning

confidence: 99%

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Targeted Disruption of Gb3/CD77 Synthase Gene Resulted in the Complete Deletion of Globo-series Glycosphingolipids and Loss of Sensitivity to Verotoxins

Okuda

Tokuda

Numata

et al. 2006

Journal of Biological Chemistry

174

166

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To examine whether globotriaosylceramide (Gb3/CD77) is a receptor for verotoxins (VTs) in vivo, sensitivity of Gb3/CD77 synthase null mutant mice to VT-2 and VT-1 was analyzed. Although wild-type mice died after administration of 0.02 g of VT-2 or 1.0 g of VT-1, the mutant mice showed no reaction to doses as much as 100 times that administered to wild types. Expression analysis of Gb3/CD77 in mouse tissues with antibody revealed that low, but definite, levels of Gb3/CD77 were expressed in the microvascular endothelial cells of the brain cortex and pia mater and in renal tubular capillaries. Corresponding to the Gb3/CD77 expression, tissue damage with edema, congestion, and cytopathic changes was observed, indicating that Gb3/CD77 (and its derivatives) exclusively function as a receptor for VTs in vivo. The lethal kinetics were similar regardless of lipopolysaccharide elimination in VT preparation, suggesting that basal Gb3/CD77 levels are sufficient for lethal effects of VTs.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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Targeted Disruption of Gb3/CD77 Synthase Gene Resulted in the Complete Deletion of Globo-series Glycosphingolipids and Loss of Sensitivity to Verotoxins

Okuda

Tokuda

Numata

et al. 2006

Journal of Biological Chemistry

174

166

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“…HUS is characterized by occlusion of the renal glomerular microvasculature with fibrin and platelets (8). In human kidneys, Gb 3 is principally expressed in the cortex, and Gb 3 expression is higher in adults than in children (19). Stx binds to distal convoluted tubules and collecting ducts of the juxtaglomerular region in both infants and adults, but more intensely in the latter (35).…”

Section: Discussionmentioning

confidence: 99%

“…The preferred receptor for Stx2e (a variant of Stx2 produced by strains of E. coli that cause edema disease of swine) is globotetraosylceramide (17,18). Humans, rabbits, and pigs have vascular receptors for Stx and develop Stxmediated vascular damage (8,17,(19)(20)(21)(22). Rabbits also have Stx receptors on intestinal villous epithelial cells, and Stx is enterotoxic (impairs NaCl absorption, causing intestinal fluid accumulation and diarrhea) in rabbits (23,24).…”

mentioning

confidence: 99%

Cattle lack vascular receptors for Escherichia coli O157:H7 Shiga toxins

Pruimboom‐Brees

Morgan

Ackermann

et al. 2000

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

175

143

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Escherichia coli O157:H7 causes Shiga toxin (Stx)-mediated vascular damage, resulting in hemorrhagic colitis and the hemolytic uremic syndrome in humans. These infections are often foodborne, and healthy carrier cattle are a major reservoir of E. coli O157:H7. We were interested in knowing why cattle are tolerant to infection with E. coli O157:H7. Cattle tissues were examined for the Stx receptor globotriaosylceramide (Gb3), for receptivity to Stx binding in vitro, and for susceptibility to the enterotoxic effects of Stx in vivo. TLC was used to detect Gb3 in tissues from a newborn calf. Gb3 was detected by TLC in kidney and brain, but not in the gastrointestinal tract. Immunohistochemistry was used to define binding of Stx1 and Stx2 overlaid onto sections from cattle tissues. Stx1 and Stx2 bound to selected tubules in the cortex of the kidney of both newborn calves (n ‫؍‬ 3) and adult cattle (n ‫؍‬ 3). Stx did not bind to blood vessels in any of the six gastrointestinal and five extraintestinal organs examined. The lack of Gb3 and of Stx receptivity in the gastrointestinal tract raised questions about the toxicity of Stx in bovine intestine. We found that neither viable E. coli O157:H7 nor Stx-containing bacterial extracts were enterotoxic (caused fluid accumulation) in ligated ileal loops in newborn calves. The lack of vascular receptors for Stx provides insight into why cattle are tolerant reservoir hosts for E. coli O157:H7.

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Intracellular targeting of the endoplasmic reticulum/nuclear envelope by retrograde transport may determine cell hypersensitivity to verotoxin via globotriaosyl ceramide fatty acid isoform traffic

1998

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The pentameric B subunit of verotoxin (VT) mediates the attachment to cell surface globotriaosyl ceramide (Gb3) to facilitate receptor-mediated endocytosis of the toxin. In highly toxin-sensitive tumor cells, the holotoxin and VT1 B subunit is targeted intracellularly to elements of the endoplasmic reticulum (ER)/nuclear membrane. In less sensitive cells, the toxin is targeted to components of the Golgi apparatus. We have studied two cell systems: the induced VT hypersensitivity of human astrocytoma cell lines cultured in the presence of sodium butyrate (compared to sodium propionate and capronate) and the increased VT sensitivity of multiple drug-resistant mutants as compared to parental human ovarian carcinoma cells. In both cases, a difference in the intracellular retrograde transport of the receptor-bound internalized toxin to the ER/nuclear envelope, as opposed to the Golgi, correlated with a >1,000-fold increase in cell sensitivity to VT. This change in intracellular routing may be due to sorting of Gb3 fatty acid isoforms, since nuclear targeting was found in turn to correlate with the preferential synthesis of Gb3 containing shorter chain (primarily C16) fatty acid species. We propose that the isoform-dependent traffic of Gb3 from the cell surface to the ER/nuclear membrane provides a new signal transduction pathway for Gb3 binding proteins.

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Verotoxin Receptor Glycolipid in Human Renal Tissue

Cited by 196 publications

References 5 publications

Targeted Disruption of Gb3/CD77 Synthase Gene Resulted in the Complete Deletion of Globo-series Glycosphingolipids and Loss of Sensitivity to Verotoxins

Targeted Disruption of Gb3/CD77 Synthase Gene Resulted in the Complete Deletion of Globo-series Glycosphingolipids and Loss of Sensitivity to Verotoxins

Cattle lack vascular receptors for Escherichia coli O157:H7 Shiga toxins

Intracellular targeting of the endoplasmic reticulum/nuclear envelope by retrograde transport may determine cell hypersensitivity to verotoxin via globotriaosyl ceramide fatty acid isoform traffic

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