1. All major cholesterol-dependent cytolysins use glycans as cellular receptors
- Author
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Bostjan Kobe, Victor J. Torres, Adrienne W. Paton, Thomas Haselhorst, James C. Paton, Josephine F. Reijneveld, Arun V. Everest-Dass, Kristina M. Boguslawski, David B. A. James, Victor Nizet, Michael P. Jennings, Mark von Itzstein, Stephan Brouwer, John M. Atack, Christine M. Gillen, Zhenyao Luo, Lucy K. Shewell, Freda E.-C. Jen, Mark J. Walker, and Christopher J. Day
- Subjects
Glycan ,Host tropism ,Receptors, Cell Surface ,Cholesterol analog ,Microbiology ,03 medical and health sciences ,Antigen ,Polysaccharides ,Lectins ,Receptor ,Research Articles ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,biology ,Cytotoxins ,030306 microbiology ,Chemistry ,Listeriolysin O ,SciAdv r-articles ,3. Good health ,Cell biology ,carbohydrates (lipids) ,Cholesterol ,biology.protein ,Streptolysin ,Cellular Tropism ,Research Article - Abstract
Eight major CDCs use glycans as cellular receptors to potentiate cytotoxicity and bind glycans and cholesterol independently., Cholesterol-dependent cytolysins (CDCs) form pores in cholesterol-rich membranes, but cholesterol alone is insufficient to explain their cell and host tropism. Here, we show that all eight major CDCs have high-affinity lectin activity that identifies glycans as candidate cellular receptors. Streptolysin O, vaginolysin, and perfringolysin O bind multiple glycans, while pneumolysin, lectinolysin, and listeriolysin O recognize a single glycan class. Addition of exogenous carbohydrate receptors for each CDC inhibits toxin activity. We present a structure for suilysin domain 4 in complex with two distinct glycan receptors, P1 antigen and αGal/Galili. We report a wide range of binding affinities for cholesterol and for the cholesterol analog pregnenolone sulfate and show that CDCs bind glycans and cholesterol independently. Intermedilysin binds to the sialyl-TF O-glycan on its erythrocyte receptor, CD59. Removing sialyl-TF from CD59 reduces intermedilysin binding. Glycan-lectin interactions underpin the cellular tropism of CDCs and provide molecular targets to block their cytotoxic activity.
- Published
- 2020
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