Endocytosis and intracellular sorting of ricin and Shiga toxin

Sandvig, Kirsten; Deurs, Bo van

doi:10.1016/0014-5793(94)00281-9

Cited by 76 publications

(53 citation statements)

References 38 publications

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“…MLIA c m bind more effectively with hydrophobic sites of intracel-1 dar membranes before translocation into the cytosol. ITs and holotoxins are internalized via a receptor-mediated pathway [16]. After binding with receptors, the conjugates progress to intracellular compartments with different pH (endosomes, lysosomes, cis-and trans-Golgi).…”

Section: Resultsmentioning

confidence: 99%

Immunotoxins containing A‐chain of mistletoe lectin I are more active than immunotoxins with ricin A‐chain

et al. 1996

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Section: Resultsmentioning

confidence: 99%

Immunotoxins containing A‐chain of mistletoe lectin I are more active than immunotoxins with ricin A‐chain

et al. 1996

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“…Shiga toxin, like ricin and cholera toxin, has no intrinsic pore-forming activity, yet all of these toxins must gain access to the cytosol (22,24). These toxins require trafficking in a circuitous route to the ER, unlike toxins that enter the cytosol directly from the plasma membrane or from the endosomal compartment.…”

Section: Discussionmentioning

confidence: 99%

Shiga Toxin Is Transported from the Endoplasmic Reticulum following Interaction with the Luminal Chaperone HEDJ/ERdj3

2005

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Shiga toxin (Stx) follows a complex intracellular pathway in order to kill susceptible cells. After binding to cell surface glycolipids, the toxin is internalized and trafficked in retrograde fashion to the endoplasmic reticulum (ER). From the ER lumen, the toxin must gain access to the cytoplasm, where it enzymatically inactivates the 28S rRNA, inhibiting protein synthesis. The host molecules involved in this pathway and the mechanisms utilized by the toxin to access the cytoplasm from the ER are largely unknown. We found that Stx is capable of energy-dependent transport across the ER lumen, as has recently been demonstrated for the cholera and ricin toxins. Genetic screening for molecules involved in Shiga toxin trafficking yielded a cDNA encoding a prematurely truncated protein. Characterization of this cDNA revealed that it encodes a novel Hsp40 chaperone, designated HEDJ or ERdj3, localized to the ER lumen, where it interacts with BiP, a molecule known to be involved in protein retrotranslocation out of the ER. We demonstrated that within the ER lumen Stx interacts with HEDJ and other chaperones known to be involved in retrotranslocation of proteins across the ER membrane. Moreover, sequential immunoprecipitation revealed that Shiga toxin was present in a complex that included HEDJ and Sec61, the translocon through which proteins are retrotranslocated to the cytoplasm. These findings suggest that HEDJ is a component of the ER quality control system and that Stx utilizes HEDJ and other ER-localized chaperones for transport from the ER lumen to the cytosol.

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“…Agents which block the endocytic acidification (chloroquine, monensin, and bafilomycin A1) and which inhibit the internalization of many toxins into the cytosol were unable to prevent epsilon-toxin cytotoxicity. Certain toxins, such as cholera toxin and Shiga toxin, are internalized by receptor-mediated endocytosis and are routed through the Golgi apparatus, since they are blocked by brefeldin A, which is known to disrupt the Golgi stacks (6,42). However, MDCK cells are resistant to brefeldin A (41), and thus the Golgi pathway cannot be explored in MDCK cells.…”

Section: Vol 179 1997 Effects Of C Perfringens Epsilon-toxin On Mdmentioning

confidence: 99%

Clostridium perfringens epsilon-toxin acts on MDCK cells by forming a large membrane complex

et al. 1997

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Epsilon-toxin is produced by. Here we present evidence that epsilon-toxin cytotoxic activity is correlated with the formation of a large membrane complex (about 155 kDa) and efflux of intracellular K ؉ without entry of the toxin into the cytosol. Epsilon-toxin induced swelling, blebbing, and lysis of MDCK cells. Iodolabeled epsilon-toxin bound specifically to MDCK cell membranes at 4 and 37°C and was associated with a large complex (about 155 kDa). The binding of epsilon-toxin to the cell surface was corroborated by immunofluorescence staining. The complex formed at 37°C was more stable than that formed at 4°C, since it was not dissociated by 5% sodium dodecyl sulfate and boiling.Epsilon-toxin is produced by Clostridium perfringens types B and D and is responsible for a rapidly fatal enterotoxemia in sheep and other animals which causes heavy economic losses (24). It is synthesized as a relatively inactive prototoxin (296 amino acids) which is converted to a highly active mature protein by proteolytic removal of a basic N-terminal peptide (13 amino acids) (3, 16).Epsilon-toxin is lethal and dermonecrotic. It has been reported to increase intestinal permeability (4), to cause kidney damage (9), to elevate blood pressure (27, 39), and to cause contraction of isolated rat ileum (40). A basic property of epsilon-toxin is that it increases vascular permeability. The toxin binds to vascular endothelial cells and causes severe vascular damage and edema in various organs (brain, heart, lung, and kidney) (5, 9). It was reported that the major pathological changes caused by enterotoxemia appear to occur in the brain (12). Moreover, it was shown that labeled toxin specifically accumulates in the brains of mice after intravenous injection and that the lethal activity of the toxin depends on its specific binding in the brain, probably to a sialoglycoprotein (28,29). Certain amino acids of epsilon-toxin, such as histidine, tryptophan, and aspartic or glutamic acid have been found to be essential for its biological activity (35)(36)(37)(38).Recently, it has been found that epsilon-toxin has 20 and 27% identity with Mtx2 and Mtx3 toxins, respectively, of Bacillus sphaericus (22, 43) and 26.5% identity with the open reading frame c53 of Bacillus thuringiensis. However, the mechanism of action of these mosquitocidal toxins is unknown.The Madin-Darby canine kidney (MDCK) cell line was found to be susceptible to epsilon-toxin. The alteration of cell viability determined by the conversion of 5-(3-carboxymethoxyphenyl)-2-(4,5-dimethylthiazolyl)-3-(4-sulfophenyl) tetrazolium to a water-soluble formazan by the mitochondrial cytochrome systems or by the neutral red assay (an indicator of lysosomal integrity) was correlated with the lethal activity of epsilon-toxin in mice (21, 30). The cytotoxic effects were found to be very rapid (2.5 min) and potentiated by EDTA (21). The morphological effects of epsilon-toxin on cells included a condensation of the nucleus and a progressive swelling of the cells (13). The permeability of polarized MD...

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Endocytosis and intracellular sorting of ricin and Shiga toxin

Cited by 76 publications

References 38 publications

Immunotoxins containing A‐chain of mistletoe lectin I are more active than immunotoxins with ricin A‐chain

Immunotoxins containing A‐chain of mistletoe lectin I are more active than immunotoxins with ricin A‐chain

Shiga Toxin Is Transported from the Endoplasmic Reticulum following Interaction with the Luminal Chaperone HEDJ/ERdj3

Clostridium perfringens epsilon-toxin acts on MDCK cells by forming a large membrane complex

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