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Delivery into cells: lessons learned from plant and bacterial toxins

Abstract

A number of protein toxins of bacterial and plant origin have cytosolic targets, and knowledge about these toxins have provided us with essential information about mechanisms that can be used to gain access to the cytosol as well as detailed knowledge about endocytosis and intracellular sorting. Such toxins include those that have two moieties, one (the B-moiety) that binds to cell surface receptors and another (the A-moiety) with enzymatic activity that enters the cytosol, as well as molecules that only have the enzymatically active moiety and therefore are inefficient in cell entry. The toxins discussed in the present article include bacterial toxins such as Shiga toxin and diphtheria toxin, as well as plant toxins such as ricin and ribosome-inactivating proteins without a binding moiety, such as gelonin. Toxins with a binding moiety can be used as vectors to translocate epitopes, intact proteins, and even nucleotides into the cytosol. The toxins fall into two main groups when it comes to cytosolic entry. Some toxins enter from endosomes in response to low endosomal pH, whereas others, including Shiga toxin and ricin, are transported all the way to the Golgi apparatus and the ER before they are translocated to the cytosol. Plant proteins such as gelonin that are without a binding moiety are taken up only by fluid-phase endocytosis, and normally they have a low toxicity. However, they can be used to test for disruption of endosomal membranes leading to cytosolic access of internalized molecules. Similarly to toxins with a binding moiety they are highly toxic when reaching the cytosol, thereby providing the investigator with an efficient tool to study endosomal disruption and induced transport to the cytosol. In conclusion, the protein toxins are useful tools to study transport and cytosolic translocation, and they can be used as vectors for transport to the interior of the cell.

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Acknowledgements

Work performed by the authors of the present article is being supported by the Norwegian and Danish Cancer Societies, the Norwegian Research Council for Science and the Humanities, The Danish Medical Research Council, The Novo Nordisk Foundation, the Jahre Foundation, and Jeanette and Søren Bothners Legacy.

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Sandvig, K., van Deurs, B. Delivery into cells: lessons learned from plant and bacterial toxins. Gene Ther 12, 865–872 (2005). https://doi.org/10.1038/sj.gt.3302525

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Keywords

  • toxin
  • Shiga toxin
  • diphtheria toxin
  • ricin
  • endocytosis

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