Membrane cytosolic translocation of verotoxin A1 subunit in target cells

Tam, Patricia J.; Lingwood, Clifford A.

doi:10.1099/mic.0.2007/006858-0

Cited by 68 publications

(78 citation statements)

References 62 publications

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“…Shiga toxin production was assayed as previously described (Karmali et al, 1985a;Tam & Lingwood, 2007). Briefly, 1.5610 4 Vero cells were seeded into 96-well tissue culture plates and grown for 24 h at 37 uC, 5 % CO 2 prior to the experiment.…”

Section: Methodsmentioning

confidence: 99%

Acid-stress-induced changes in enterohaemorrhagic Escherichia coli O157 : H7 virulence

et al. 2009

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Enterohaemorrhagic Escherichia coli (EHEC) O157 : H7 is naturally exposed to a wide variety of stresses including gastric acid shock, and yet little is known about how this stress influences virulence. This study investigated the impact of acid stress on several critical virulence properties including survival, host adhesion, Shiga toxin production, motility and induction of host-cell apoptosis. Several acid-stress protocols with relevance for gastric passage as well as external environmental exposure were included. Acute acid stress at pH 3 preceded by acid adaptation at pH 5 significantly enhanced the adhesion of surviving organisms to epithelial cells and bacterial induction of host-cell apoptosis. Motility was also significantly increased after acute acid stress. Interestingly, neither secreted nor periplasmic levels of Shiga toxin were affected by acid shock. Pretreatment of bacteria with erythromycin eliminated the acid-induced adhesion enhancement, suggesting that de novo protein synthesis was required for the enhanced adhesion of acidshocked organisms. DNA microarray was used to analyse the transcriptome of an EHEC O157 : H7 strain exposed to three different acid-stress treatments. Expression profiles of acidstressed EHEC revealed significant changes in virulence factors associated with adhesion, motility and type III secretion. These results document profound changes in the virulence properties of EHEC O157 : H7 after acid stress, provide a comprehensive genetic analysis to substantiate these changes and suggest strategies that this pathogen may use during gastric passage and colonization in the human gastrointestinal tract.

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Section: Methodsmentioning

confidence: 99%

Acid-stress-induced changes in enterohaemorrhagic Escherichia coli O157 : H7 virulence

et al. 2009

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“…One possibility is that Stx uses the same retrotranslocon (Sec61) as is apparently being exploited by cholera toxin and ricin to gain access to the cytosol [119,120]. However, it is unclear whether StxA can interact with Sec61 or not [112,113]. Alternatively, Stx might use other putative ER retrotranslocon channels, such as those constituted by the derlin family.…”

Section: Translocation To the Cytosolmentioning

confidence: 99%

“…How the disulfide bridge is reduced is not known, but in analogy with cholera toxin, whose active A 1 fragment also needs to be cleaved from its disulfide-linked A 2 fragment, it is possible that the reduction also of StxA is carried out by the ER-resident enzyme protein disulfide isomerase [110,111]. In Vero cells (which contain furin) it was demonstrated that the vast majority of StxA in the cells was not reduced and only the A 1 chain could be detected in the cytosol [112]. However, it can not be excluded that also the whole A-chain can be translocated from the ER to the cytosol.…”

Section: Translocation To the Cytosolmentioning

confidence: 99%

“…Moreover, in Vero cells a Stx-mutant that lacks the furin cleavage site was shown to be processed in a manner that was sensitive to inhibitors of the cytosolic enzyme calpain [114], indicating that also in vivo, the whole A-chain may translocate to the cytosol. Given that the A-chain stays attached to the pentameric B-moiety (which again is most likely still bound to Gb3) all the way to the ER [112], it remains to be demonstrated how this intoxication process occurs.…”

Section: Translocation To the Cytosolmentioning

confidence: 99%

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The Intracellular Journey of Shiga Toxins

Torgersen¹

2013

TOTNJ

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Abstract:The Shiga toxin family consists of Shiga toxin (Stx) that is produced as a virulence factor by Shigella dysenteriae, and the Shiga-like toxins produced by certain strains of enterohemorrhagic E. coli as well as by some other types of bacteria. Infection with bacteria producing these toxins is a threat to human health even in industrialized countries, as the initial diarrhea caused by the infection might be followed by a complication named hemolytic uremic syndrome. The Shiga toxins consist of a binding moiety that in most cases binds to the glycosphingolipid Gb3 on the surface of susceptible cells, and an A-moiety responsible for the toxic effect in the cytosol. In order to reach its cytosolic target, the toxin must be internalized and then transported via the retrograde pathway to the Golgi complex and further to the endoplasmic reticulum. From the endoplasmic reticulum the enzymatically active part of the A-moiety is translocated to the cytosol, and cellular protein synthesis is inhibited. Although the Shiga toxins are involved in disease, they may also be exploited for medical diagnosis and treatment. Interestingly, the toxin receptor, Gb3, has a limited expression in normal tissues, but is overexpressed in several types of cancer. Thus, the use of Shiga toxin, or the binding part of the toxin, has great potential in cancer diagnostics and treatment. Furthermore, studies of the various uptake mechanisms and intracellular transport pathways exploited by the toxins, provide important insight in basic cell biology processes.

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“…The ER is the site International Letters of Natural Sciences Vol. 34of disulfide bond reduction, unfolding of the A1-fragment and retrotranslocation of the A1-fragment possibly via the Sec61 translocon into the cytoplasm (Lord et al, 2005;Tam and Lingwood, 2007). The A1-fragment possesses N-glycosidase activity and cleaves a single adenine residue from the 28S rRNA component of eukaryotic ribosomes (Endo et al, 1988).…”

Section: Shiga Toxinmentioning

confidence: 99%

Molecular Aspects of Effect of Shiga Toxin in Humans - A Review

Pal¹

2015

ILNS

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Shiga toxins belonging to a family of structurally and functionally related protein toxins serve as the key virulence factors for pathogenecity of the virulent enteric bacterial strains namely Shigella dysenteriae serotype 1 including Shiga toxin-producing Escherichia coli (STEC). S. dysenteriae type 1 isolates remain major public health concerns due to their widespread outbreaks and the severity of extra-intestinal diseases, including acute renal failure and also affects the central nervous system. Despite practicing improved hygienic conditions and regulating food and drinking water safety, the enteric pathogens are imposing a major threat in the well being of the human society. Shiga toxin on entry into host cells' endoplasmic reticulum (ER) activates the stress response in ER and inhibits protein synthesis by catalytic inactivation of eukaryotic ribosomes. In many cell types shiga toxins trigger apoptosis. Recent studies have shown that shiga toxins induce autophagy which activates different signaling pathways in toxin-sensitive and toxin-resistant human cells. In this review the molecular basis of Shiga toxins' effect on host cell leading to manifestation of the infection in affected individuals are discussed with an emphasis on recent findings.

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Membrane cytosolic translocation of verotoxin A1 subunit in target cells

Cited by 68 publications

References 62 publications

Acid-stress-induced changes in enterohaemorrhagic Escherichia coli O157 : H7 virulence

Acid-stress-induced changes in enterohaemorrhagic Escherichia coli O157 : H7 virulence

The Intracellular Journey of Shiga Toxins

Molecular Aspects of Effect of Shiga Toxin in Humans - A Review

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