Ricin is one of the most feared bioweapons in the world due to its extreme toxicity and easy access. Since no antidote exists, it is of paramount importance to identify the pathways underlying ricin toxicity. Here, we demonstrate that the Golgi GDP-fucose transporter Slc35c1 and fucosyltransferase Fut9 are key regulators of ricin toxicity. Genetic and pharmacological inhibition of fucosylation renders diverse cell types resistant to ricin via deregulated intracellular trafficking. Importantly, cells from a patient with SLC35C1 deficiency are also resistant to ricin. Mechanistically, we confirm that reduced fucosylation leads to increased sialylation of Lewis X structures and thus masking of ricin-binding sites. Inactivation of the sialyltransferase responsible for modifications of Lewis X (St3Gal4) increases the sensitivity of cells to ricin, whereas its overexpression renders cells more resistant to the toxin. Thus, we have provided unprecedented insights into an evolutionary conserved modular sugar code that can be manipulated to control ricin toxicity.

中文翻译：

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蓖麻毒素毒性的重要糖类代码。

蓖麻毒素因其极高的毒性和易于获取而成为世界上最令人担忧的生物武器之一。由于不存在解毒剂，因此识别蓖麻毒蛋白毒性的潜在途径至关重要。在这里，我们证明高尔基GDP岩藻糖转运蛋白Slc35c1和岩藻糖基转移酶Fut9是蓖麻毒蛋白毒性的关键调节因子。岩藻糖基化的遗传和药理学抑制作用使多种细胞类型通过失控的细胞内运输而对蓖麻毒蛋白具有抗性。重要的是，来自SLC35C1缺乏症患者的细胞对蓖麻毒蛋白也有抗性。从机理上讲，我们确认岩藻糖基化程度降低导致Lewis X结构的唾液酸化程度增加，从而掩盖了蓖麻毒蛋白结合位点。负责修饰Lewis X（St3Gal4）的唾液酸转移酶的失活增加了细胞对蓖麻毒蛋白的敏感性，而其过表达使细胞对毒素更具抵抗力。因此，我们对进化保守的模块化糖代码提供了空前的见识，可将其编码以控制蓖麻毒蛋白毒性。