The mode of action of Shiga toxin on peptide elongation of eukaryotic protein synthesis

Obrig, Tom G.; Moran, Timothy P.; Brown, J E

doi:10.1042/bj2440287

Cited by 166 publications

(97 citation statements)

References 35 publications

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“…All shiga toxins consist of a single A subunit in association with several pentamer B subunits (8)(9)(10). The A subunit as a ribosomal RNA N-glycosidase removes the adenine of the 28S RNA within the 60S ribosomal subunit (11), thereby rendering ribosomes inactive for protein synthesis (12). In contrast, functionality of the B subunit requires binding to the plasma membrane and internalization (4).…”

Section: Introductionmentioning

confidence: 99%

Globotriaosylceramide (Gb3) content in HeLa cells is correlated to Shiga toxin-induced cytotoxicity and Gb3 synthase expression

Shin

Ishii²,

Shin³

et al. 2009

BMB Reports

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Section: Introductionmentioning

confidence: 99%

Globotriaosylceramide (Gb3) content in HeLa cells is correlated to Shiga toxin-induced cytotoxicity and Gb3 synthase expression

Shin

Ishii²,

Shin³

et al. 2009

BMB Reports

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“…The ribosome-inactivating function of VTA has been well characterized (Obrig et al, 1987;Saxena et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Membrane cytosolic translocation of verotoxin A1 subunit in target cells

Tam

Lingwood

2007

Microbiology

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“…Intracellularly the A subunit is proteolytically nicked, binds to 60S ribosomes, and thereby inhibits protein synthesis leading to cell death. 18 Thrombocytopenia is an important feature of HUS. Platelets are consumed in small thrombi, and these thrombi may compromise the blood supply to various organs, particularly the kidney.…”

Section: Introductionmentioning

confidence: 99%

“…16,17 We propose that these discrepancies may result from methodological differences related to the length of incubation of platelets with Stx and the temperature at incubation. Specifically, we incubated platelets with Stx at 37°C and believe that this enabled binding to occur.In vitro and in vivo studies have shown that Stx is capable of inducing cell death by intracellular blocking of protein synthesis 18 and by inducing apoptosis. 6,7,50,51 Recent studies have also reported that Stx is capable of activating intestinal epithelial cells, monocytes, and monocytic cell lines to produce and secrete cytokines, 44,52,53 suggesting that the toxin may have stimulatory effects as well.…”

mentioning

confidence: 99%

Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome

Karpman

Papadopoulou

Nilsson

et al. 2001

Blood

129

117

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Thrombocytopenia caused by platelet consumption in thrombi is a major manifestation of hemolytic uremic syndrome (HUS) associated with Shiga toxin (Stx) producing Escherichia coli. Platelets have glycosphingolipid receptors capable of binding Stx, but a direct interaction between the toxin and platelets, leading to platelet activation, has not been reported. In this study, it is shown that Stx1 and its B (binding) subunit (Stx1B), at 10 pg/mL to 10 ng/mL, bound to platelets. IntroductionShiga toxin (Stx)-producing Escherichia coli (STEC) have been associated with cases of hemolytic uremic syndrome (HUS). Microangiopathic hemolytic anemia, acute renal failure, and thrombocytopenia characterize this syndrome. Stx has been specifically implicated as a causal factor 1 of HUS because cases of the disease have been associated with Stx-producing strains, 2 the toxin has been identified in the kidney of a patient with HUS, 3 and the toxin has been found to be cytotoxic for renal endothelial and epithelial cells. [4][5][6][7][8] In addition, animal models have reproduced aspects of HUS using wild-type bacteria that produce the toxin 9,10 or purified toxin. 11 The toxin is composed of 5 B, or binding, subunits and 1 enzymatically active A subunit. 12 The molecular weight of the A subunit is 33 000 kd, and that of the pentameric B subunit is approximately 35 000 kd. 13 The B subunit (StxB) binds to a glycosphingolipid receptor on cell membranes, globotriaosyl ceramide (Gb3), containing the terminal disaccharide galactose ␣(1-4) galactose ␤. 14 A recent study showed that Stx could bind to platelets through Gb3 and a novel platelet glycosphingolipid termed band 0.03. 15 Other studies have not been able to reproduce these results. 16,17 Binding to the cell mediates endocytosis of the holotoxin. Intracellularly the A subunit is proteolytically nicked, binds to 60S ribosomes, and thereby inhibits protein synthesis leading to cell death. 18 Thrombocytopenia is an important feature of HUS. Platelets are consumed in small thrombi, and these thrombi may compromise the blood supply to various organs, particularly the kidney. The mechanism by which these thrombi are formed is unclear, and platelet activation has been suggested. Studies performed on platelets from patients with HUS showed impaired aggregating responses 19,20 and reduced ␤-thromboglobulin (␤-TG) content. 19 Platelet-derived products such as ␤-TG, platelet factor 4, 21 and soluble P-selectin 22 were found to be elevated during acute HUS. Furthermore, changes in platelet ultramorphology were noted. 23 Increased platelet-derived microvesicles were found in these patients, 24 indicating platelet activation. Plasma from patients with HUS increased aggregation of normal platelets, but the factor causing this was not determined. 25 Several previous studies have investigated a direct interaction between Stx and platelets. Culture filtrates from Stx-producing E coli were found to induce platelet-aggregating activity, 26 but purified Stx did not increase platelet aggregation 16...

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The mode of action of Shiga toxin on peptide elongation of eukaryotic protein synthesis

Cited by 166 publications

References 35 publications

Globotriaosylceramide (Gb3) content in HeLa cells is correlated to Shiga toxin-induced cytotoxicity and Gb3 synthase expression

Globotriaosylceramide (Gb3) content in HeLa cells is correlated to Shiga toxin-induced cytotoxicity and Gb3 synthase expression

Membrane cytosolic translocation of verotoxin A1 subunit in target cells

Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome

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