Inhibition of Retrograde Transport Protects Mice from Lethal Ricin Challenge
Inhibition of Retrograde Transport Protects Mice from Lethal Ricin Challenge
复制标题
DOI：
10.1016/j.cell.2010.01.043
复制
发表时间：
2010-04-16
期刊：
影响因子：
64.5
通讯作者：
Barbier, Julien
中科院分区：
文献类型：
--
作者：
Stechmann, Bahne;Bai, Siau-Kun;Barbier, Julien
细菌志贺样毒素是一种对全球公共卫生构成重大威胁的毒力因子，而植物毒素蓖麻毒素是一种潜在的生物恐怖武器。为了接近它们的胞质靶标核糖体RNA，这些毒素遵循从质膜到内质网的逆行运输路线，通过内体和高尔基体。在这里，我们使用高通量筛选来鉴定保护细胞免受蓖麻毒素和志贺样毒素侵害的小分子抑制剂。我们鉴定了两种化合物，其在早期内体-TGN界面处选择性地阻断逆行毒素运输，而不影响隔室形态、内源性逆行货物或其他运输步骤，证明了出乎意料的选择性程度和缺乏毒性。在小鼠中，一种化合物显然可以防止致命的蓖麻毒素鼻暴露。我们的工作发现了第一个在动物实验中对蓖麻毒素有效的小分子，并将逆行途径确定为潜在的治疗靶点。
Bacterial Shiga-like toxins are virulence factors that constitute a significant public health threat worldwide, and the plant toxin ricin is a potential bioterror weapon. To gain access to their cytosolic target, ribosomal RNA, these toxins follow the retrograde transport route from the plasma membrane to the endoplasmic reticulum, via endosomes and the Golgi apparatus. Here, we used high-throughput screening to identify small molecule inhibitors that protect cells from ricin and Shiga-like toxins. We identified two compounds that selectively block retrograde toxin trafficking at the early endosome-TGN interface, without affecting compartment morphology, endogenous retrograde cargos, or other trafficking steps, demonstrating an unexpected degree of selectivity and lack of toxicity. In mice, one compound clearly protects from lethal nasal exposure to ricin. Our work discovers the first small molecule that shows efficacy against ricin in animal experiments and identifies the retrograde route as a potential therapeutic target.