Targeting the Early Endosome-to-Golgi Transport of Shiga Toxins as a Therapeutic Strategy

Li, Danyang; Selyunin, Andrey S.; Mukhopadhyay, Somshuvra

doi:10.3390/toxins12050342

Cited by 11 publications

(31 citation statements)

References 85 publications

(184 reference statements)

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“…It should be noted that GPP130 does not interact with Shiga-like toxin 2 (Stx2), which is important for disease caused by toxin-secreting E. coli species, and the mechanism behind transport of this toxin to the Golgi is not known. Over the years, different kinases, sorting nexins, Rab-proteins, Golgins, and SNARE-complexes have been shown to be involved in endosome to Golgi transport (for review, see [95,96]). For instance, in the case of Shiga toxin, Rab6A' was found to be required for endosome to Golgi transport [97,98].…”

Section: Endosome To Golgi Transportmentioning

confidence: 99%

“…Several different molecules have now been identified to be involved in retrograde transport and for translocation of the enzymatically active part of the toxins (for review, see [95,96]). Again, it is important to be aware of the ability of cells to induce compensatory processes.…”

Section: Retrograde Toxin Transport From the Golgi To The Er And Translocation To The Cytosolmentioning

confidence: 99%

“…In a review by Kavaliauskiene et al [72], chloroquine and hydroxychloroquine, both drugs used in humans, were able to protect against both Shiga toxin and Stx2. In a recent review by Selyunin and Mykhopadhyay [95], several other drugs, which are all approved for human use, were also described. However, it is not clear whether all these drugs act in a similar manner.…”

Section: Retrograde Toxin Transport From the Golgi To The Er And Translocation To The Cytosolmentioning

confidence: 99%

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The Protein Toxins Ricin and Shiga Toxin as Tools to Explore Cellular Mechanisms of Internalization and Intracellular Transport

Sandvig

Kavaliauskiene

Skotland

2021

Toxins

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Protein toxins secreted by bacteria and found in plants can be threats to human health. However, their extreme toxicity can also be exploited in different ways, e.g., to produce hybrid toxins directed against cancer cells and to study transport mechanisms in cells. Investigations during the last decades have shown how powerful these molecules are as tools in cell biological research. Here, we first present a partly historical overview, with emphasis on Shiga toxin and ricin, of how such toxins have been used to characterize processes and proteins of importance for their trafficking. In the second half of the article, we describe how one can now use toxins to investigate the role of lipid classes for intracellular transport. In recent years, it has become possible to quantify hundreds of lipid species using mass spectrometry analysis. Thus, it is also now possible to explore the importance of lipid species in intracellular transport. The detailed analyses of changes in lipids seen under conditions of inhibited toxin transport reveal previously unknown connections between syntheses of lipid classes and demonstrate the ability of cells to compensate under given conditions.

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Section: Endosome To Golgi Transportmentioning

confidence: 99%

Section: Retrograde Toxin Transport From the Golgi To The Er And Translocation To The Cytosolmentioning

confidence: 99%

Section: Retrograde Toxin Transport From the Golgi To The Er And Translocation To The Cytosolmentioning

confidence: 99%

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The Protein Toxins Ricin and Shiga Toxin as Tools to Explore Cellular Mechanisms of Internalization and Intracellular Transport

Sandvig

Kavaliauskiene

Skotland

2021

Toxins

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“…STx1 and STx2 are AB 5 toxins formed by the association of an enzymatically active A-subunit, which kills host cells by blocking ribosomal protein synthesis, with a B-subunit pentamer, which mediates retrograde trafficking from the cell exterior to the cytosol [12][13][14]. STx1 is essentially identical to STx produced by Shigella bacteria (the only difference is a single conservative serine-to-threonine substitution in the A-subunit) while STx2 shares~55% sequence identity with STx/STx1 [13,14]. The trafficking of STx/STx1 has been extensively characterized.…”

Section: Introductionmentioning

confidence: 99%

“…The trafficking of STx/STx1 has been extensively characterized. After endocytosis, STx/STx1 sequentially transits through early endosomes, the Golgi apparatus, and the endoplasmic reticulum from where the A-subunit translocates to the cytoplasm [13,14]. Direct transport from early endosomes to the Golgi apparatus allows the toxin to avoid degradation in late endosomes/lysosomes [13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen Derivatives Alter Retromer-Dependent Endosomal Tubulation and Sorting to Block Retrograde Trafficking of Shiga Toxins

Selyunin

Nieves-Merced

et al. 2021

Toxins

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Shiga toxin 1 and 2 (STx1 and STx2) undergo retrograde trafficking to reach the cytosol of cells where they target ribosomes. As retrograde trafficking is essential for disease, inhibiting STx1/STx2 trafficking is therapeutically promising. Recently, we discovered that the chemotherapeutic drug tamoxifen potently inhibits the trafficking of STx1/STx2 at the critical early endosome-to-Golgi step. We further reported that the activity of tamoxifen against STx1/STx2 is independent of its selective estrogen receptor modulator (SERM) property and instead depends on its weakly basic chemical nature, which allows tamoxifen to increase endolysosomal pH and alter the recruitment of retromer to endosomes. The goal of the current work was to obtain a better understanding of the mechanism of action of tamoxifen against the more disease-relevant toxin STx2, and to differentiate between the roles of changes in endolysosomal pH and retromer function. Structure activity relationship (SAR) analyses revealed that a weakly basic amine group was essential for anti-STx2 activity. However, ability to deacidify endolysosomes was not obligatorily necessary because a tamoxifen derivative that did not increase endolysosomal pH exerted reduced, but measurable, activity. Additional assays demonstrated that protective derivatives inhibited the formation of retromer-dependent, Golgi-directed, endosomal tubules, which mediate endosome-to-Golgi transport, and the sorting of STx2 into these tubules. These results identify retromer-mediated endosomal tubulation and sorting to be fundamental processes impacted by tamoxifen; provide an explanation for the inhibitory effect of tamoxifen on STx2; and have important implications for the therapeutic use of tamoxifen, including its development for treating Shiga toxicosis.

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Targeting the Inside of Cells with Biologicals: Toxin Routes in a Therapeutic Context

Ruschig

Marschall

2023

BioDrugs

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Numerous toxins translocate to the cytosol in order to fulfil their function. This demonstrates the existence of routes for proteins from the extracellular space to the cytosol. Understanding these routes is relevant to multiple aspects related to therapeutic applications. These include the development of anti-toxin treatments, the potential use of toxins as shuttles for delivering macromolecular cargo to the cytosol or the use of drugs based on toxins. Compared with other strategies for delivery, such as chemicals as carriers for macromolecular delivery or physical methods like electroporation, toxin routes present paths into the cell that potentially cause less damage and can be specifically targeted. The efficiency of delivery via toxin routes is limited. However, low-delivery efficiencies can be entirely sufficient, if delivered cargoes possess an amplification effect or if very few molecules are sufficient for inducing the desired effects. This is known for example from RNA-based vaccines that have been developed during the coronavirus disease 2019 pandemic as well as for other approved RNA-based drugs, which elicited the desired effect despite their typically low delivery efficiencies. The different mechanisms by which toxins enter cells may have implications for their technological utility. We review the mechanistic principles of the translocation pathway of toxins from the extracellular space to the cytosol, the delivery efficiencies, and therapeutic strategies or applications that exploit toxin routes for intracellular delivery.

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Targeting the Early Endosome-to-Golgi Transport of Shiga Toxins as a Therapeutic Strategy

Cited by 11 publications

References 85 publications

The Protein Toxins Ricin and Shiga Toxin as Tools to Explore Cellular Mechanisms of Internalization and Intracellular Transport

The Protein Toxins Ricin and Shiga Toxin as Tools to Explore Cellular Mechanisms of Internalization and Intracellular Transport

Tamoxifen Derivatives Alter Retromer-Dependent Endosomal Tubulation and Sorting to Block Retrograde Trafficking of Shiga Toxins

Targeting the Inside of Cells with Biologicals: Toxin Routes in a Therapeutic Context

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