Verotoxin Receptor-Based Pathology and Therapies

Lingwood, Clifford A.

doi:10.3389/fcimb.2020.00123

Cited by 24 publications

(42 citation statements)

References 165 publications

(170 reference statements)

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“…Stxs belong to the group of AB 5 enterotoxins [ 7 ]. The B-pentamer of the Stx1a and Stx2a subtypes preferentially binds to the glycosphingolipid (GSL) globotriaosylceramide (Gb3Cer) and to less extent to globotetraosylceramide (Gb4Cer) primarily found in human endothelial cells of various vascular beds [ 8 , 9 , 10 , 11 , 12 , 13 ]. Subsequent endocytosis of the toxin–GSL complex and retrograde transport occurs by multifarious endocytic routes directing the toxin via early endosomes through the Golgi apparatus to the endoplasmic reticulum [ 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…It is generally accepted that Stxs target mainly microvascular endothelial cells of the renal glomeruli and the brain in humans [ 1 , 13 , 18 , 37 , 38 ], although evidence has been provided in an ex vivo model using human hematopoietic stem/progenitor cells that erythropoiesis, which takes place in the bone marrow, may be affected by Stx [ 39 , 40 ]. Thus, Stx-mediated toxicity towards erythroblasts during the course of erythropoiesis might contribute to anemia observed during manifestation of STEC-HUS.…”

Section: Introductionmentioning

confidence: 99%

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Shiga Toxin (Stx)-Binding Glycosphingolipids of Primary Human Renal Cortical Epithelial Cells (pHRCEpiCs) and Stx-Mediated Cytotoxicity

Detzner

Krojnewski

Pohlentz

et al. 2021

Toxins

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Human kidney epithelial cells are supposed to be directly involved in the pathogenesis of the hemolytic–uremic syndrome (HUS) caused by Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli (EHEC). The characterization of the major and minor Stx-binding glycosphingolipids, (GSLs) globotriaosylceramide (Gb3Cer) and globotetraosylceramide (Gb4Cer), respectively, of primary human renal cortical epithelial cells (pHRCEpiCs) revealed GSLs with Cer (d18:1, C16:0), Cer (d18:1, C22:0), and Cer (d18:1, C24:1/C24:0) as the dominant lipoforms. Using detergent-resistant membranes (DRMs) and non-DRMs, Gb3Cer and Gb4Cer prevailed in the DRM fractions, suggesting their association with microdomains in the liquid-ordered membrane phase. A preference of Gb3Cer and Gb4Cer endowed with C24:0 fatty acid accompanied by minor monounsaturated C24:1-harboring counterparts was observed in DRMs, whereas the C24:1 fatty acid increased in relation to the saturated equivalents in non-DRMs. A shift of the dominant phospholipid phosphatidylcholine with saturated fatty acids in the DRM to unsaturated species in the non-DRM fractions correlated with the GSL distribution. Cytotoxicity assays gave a moderate susceptibility of pHRCEpiCs to the Stx1a and Stx2a subtypes when compared to highly sensitive Vero-B4 cells. The results indicate that presence of Stx-binding GSLs per se and preferred occurrence in microdomains do not necessarily lead to a high cellular susceptibility towards Stx.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Shiga Toxin (Stx)-Binding Glycosphingolipids of Primary Human Renal Cortical Epithelial Cells (pHRCEpiCs) and Stx-Mediated Cytotoxicity

Detzner

Krojnewski

Pohlentz

et al. 2021

Toxins

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“…Overall, these toxins have shown new potential therapeutic alternatives in autoimmune and inflammatory diseases, cancer, genetic protein misfolding diseases, movement disorders, and in vaccine development. Although many examples used these three highlighted toxins, several other AB toxins have been shown to have similar characteristics in therapy, such as Shiga toxin and diphtheria toxin, further widening the range of therapeutic possibilities [ 109 , 110 ]. For example, these toxins target different cell types depending on the expression of their receptor.…”

Section: Discussionmentioning

confidence: 99%

Harnessing the Membrane Translocation Properties of AB Toxins for Therapeutic Applications

Piot

Goot

Sergeeva

2021

Toxins

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Over the last few decades, proteins and peptides have become increasingly more common as FDA-approved drugs, despite their inefficient delivery due to their inability to cross the plasma membrane. In this context, bacterial two-component systems, termed AB toxins, use various protein-based membrane translocation mechanisms to deliver toxins into cells, and these mechanisms could provide new insights into the development of bio-based drug delivery systems. These toxins have great potential as therapies both because of their intrinsic properties as well as the modular characteristics of both subunits, which make them highly amenable to conjugation with various drug classes. This review focuses on the therapeutical approaches involving the internalization mechanisms of three representative AB toxins: botulinum toxin type A, anthrax toxin, and cholera toxin. We showcase several specific examples of the use of these toxins to develop new therapeutic strategies for numerous diseases and explain what makes these toxins promising tools in the development of drugs and drug delivery systems.

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“…Shiga toxins or verotoxins are produced by a number of bacteria, including enterotoxigenic Escherichia coli . Shiga toxins STx1 and STx2 bind to Gb3 of the Globo series GSLs ( Figure 1 C), which contain the Galα1-4 linkage to LacCer [ 51 ]. Gb3 is abundant in the kidney and toxin binding can induce hemolytic uremic syndrome.…”

Section: Glycosphingolipidsmentioning

confidence: 99%

Metabolism of Glycosphingolipids and Their Role in the Pathophysiology of Lysosomal Storage Disorders

Ryckman

Brockhausen

Walia

2020

IJMS

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Glycosphingolipids (GSLs) are a specialized class of membrane lipids composed of a ceramide backbone and a carbohydrate-rich head group. GSLs populate lipid rafts of the cell membrane of eukaryotic cells, and serve important cellular functions including control of cell–cell signaling, signal transduction and cell recognition. Of the hundreds of unique GSL structures, anionic gangliosides are the most heavily implicated in the pathogenesis of lysosomal storage diseases (LSDs) such as Tay-Sachs and Sandhoff disease. Each LSD is characterized by the accumulation of GSLs in the lysosomes of neurons, which negatively interact with other intracellular molecules to culminate in cell death. In this review, we summarize the biosynthesis and degradation pathways of GSLs, discuss how aberrant GSL metabolism contributes to key features of LSD pathophysiology, draw parallels between LSDs and neurodegenerative proteinopathies such as Alzheimer’s and Parkinson’s disease and lastly, discuss possible therapies for patients.

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Verotoxin Receptor-Based Pathology and Therapies

Cited by 24 publications

References 165 publications

Shiga Toxin (Stx)-Binding Glycosphingolipids of Primary Human Renal Cortical Epithelial Cells (pHRCEpiCs) and Stx-Mediated Cytotoxicity

Shiga Toxin (Stx)-Binding Glycosphingolipids of Primary Human Renal Cortical Epithelial Cells (pHRCEpiCs) and Stx-Mediated Cytotoxicity

Harnessing the Membrane Translocation Properties of AB Toxins for Therapeutic Applications

Metabolism of Glycosphingolipids and Their Role in the Pathophysiology of Lysosomal Storage Disorders

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