Abstract
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.
Highlights
Infections caused by Shigella bacteria that produce Shiga toxin (STx) and Shiga toxin-producingEscherichia coli that produce Shiga toxin 1 and 2 (STx1 and STx2) are major causes of water- and food-borne disease in the world [1,2]
HeLa cells, STxB/STx1B is associated with cholesterol-rich membrane microdomains, and disruption of these microdomains by cholesterol extraction strongly inhibits the early endosome-to-Golgi of these microdomains by cholesterol extraction strongly inhibits the early endosome-to-Golgi transport of STxB/STx1B [28]
Mechanistic assays in cell culture revealed that manganese blocks the early endosome-to-Golgi transport of STxB/STx1B; under these conditions, STxB/STx1B is rerouted to late endosomes/lysosomes and degraded (Figure 2B) [19]
Summary
Infections caused by Shigella bacteria that produce Shiga toxin (STx) and Shiga toxin-producing. With STEC infections, STx2 is the more disease-relevant toxin; the identity with STx and STx1 [9,11]. The steps involved are, sequentially, binding to globotriaosylceramide, the cell-surface glycosphingolipid receptor for the toxins, followed by endocytosis and internalization to early glycosphingolipid receptor for the toxins, followed by endocytosis and internalization to early endosomes, direct transit from early endosomes to the Golgi apparatus, and delivery to the endosomes, direct transit from early endosomes to the Golgi apparatus, and delivery to the endoplasmic endoplasmic reticulum from where the A-subunits are translocated to the cytosol (Figure 1A) [9,14–. As retrograde trafficking is essential for toxicity, there is a high interest there is a high interest in developing inhibitors of toxin transport for therapy [9,17,18,19,20].
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