Institute for Glycomics, Griffith University, Gold Coast, QLD 4222, Australia.
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
Sci Adv. 2020 May 22;6(21):eaaz4926. doi: 10.1126/sciadv.aaz4926. eCollection 2020 May.
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, P 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 -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.
胆固醇依赖性细胞溶素 (CDCs) 在富含胆固醇的膜中形成孔，但胆固醇本身不足以解释其细胞和宿主趋向性。在这里，我们表明所有 8 种主要的 CDC 都具有高亲和力的凝集素活性，可将聚糖鉴定为候选细胞受体。链球菌溶血素 O、阴道溶素和产气荚膜梭菌溶素 O 结合多种聚糖，而肺炎球菌溶血素、溶菌素和李斯特菌溶血素 O 识别单一聚糖类。添加每种 CDC 的外源碳水化合物受体可抑制毒素活性。我们展示了 suilysin 结构域 4 与两种不同聚糖受体 P 抗原和 αGal/Galili 的复合物结构。我们报告了胆固醇和胆固醇类似物孕烯醇酮硫酸盐的广泛结合亲和力，并表明 CDC 独立地结合聚糖和胆固醇。中介溶素结合到其红细胞受体 CD59 上的唾液酸-TF-聚糖。从 CD59 上除去唾液酸-TF 会降低中介溶素的结合。糖-凝集素相互作用是 CDC 细胞趋向性的基础，并为阻断其细胞毒性活性提供了分子靶标。
