Targeting the Early Endosome-to-Golgi Transport of Shiga Toxins as a Therapeutic Strategy
Division of Pharmacology & Toxicology, College of Pharmacy, Institute for Cellular & Molecular Biology, and Institute for Neuroscience, The University of Texas at Austin, Austin, TX 78712, USA
Author to whom correspondence should be addressed.
Toxins 2020, 12(5), 342; https://doi.org/10.3390/toxins12050342
Received: 2 May 2020 / Revised: 19 May 2020 / Accepted: 20 May 2020 / Published: 22 May 2020
(This article belongs to the Special Issue Inhibitors and Countermeasures against Bacterial and Plant Toxins)
Shiga toxin (STx) produced by Shigella and closely related Shiga toxin 1 and 2 (STx1 and STx2) synthesized by Shiga toxin-producing Escherichia coli (STEC) are bacterial AB5 toxins. All three toxins target kidney cells and may cause life-threatening renal disease. While Shigella infections can be treated with antibiotics, resistance is increasing. Moreover, antibiotic therapy is contraindicated for STEC, and there are no definitive treatments for STEC-induced disease. To exert cellular toxicity, STx, STx1, and STx2 must undergo retrograde trafficking to reach their cytosolic target, ribosomes. Direct transport from early endosomes to the Golgi apparatus is an essential step that allows the toxins to bypass degradative late endosomes and lysosomes. The essentiality of this transport step also makes it an ideal target for the development of small-molecule inhibitors of toxin trafficking as potential therapeutics. Here, we review the recent advances in understanding the molecular mechanisms of the early endosome-to-Golgi transport of STx, STx1, and STx2, as well as the development of small-molecule inhibitors of toxin trafficking that act at the endosome/Golgi interface.