Autocatalytic cleavage of Clostridium difficile toxin
Autocatalytic cleavage of Clostridium difficile toxin
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DOI：
10.1038/nature05622
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发表时间：
2007-03-22
期刊：
影响因子：
64.8
通讯作者：
von Eichel-Streiber, Christoph
中科院分区：
文献类型：
--
作者：
Reineke, Jessica;Tenzer, Stefan;von Eichel-Streiber, Christoph
艰难梭菌是院内感染性腹泻和伪膜性结肠炎的病原体，具有两种主要毒力因子：大梭菌细胞毒素A和B。已经提出毒素B在其细胞摄取期间被真核靶细胞的胞质因子切割。在这里，我们报告，不仅毒素B，而且所有其他大梭菌细胞毒素的裂解，是一个自催化过程依赖于宿主胞质肌醇磷酸辅因子。天冬氨酸蛋白酶的共价抑制剂，1，2-环氧-3-（p-硝基苯氧基）丙烷，完全阻断毒素B对培养细胞的功能，并用于确定其催化活性的蛋白酶位点。据我们所知，这是第一个报告的细菌毒素，使用真核细胞的信号诱导蛋白水解，以提供其毒性结构域到靶细胞的胞质溶胶。在我们的数据的基础上，我们提出了一个综合模型的摄取和肌醇磷酸诱导的激活毒素B。
Clostridium difficile, the causative agent of nosocomial antibiotic-associated diarrhoea and pseudomembranous colitis, possesses two main virulence factors: the large clostridial cytotoxins A and B. It has been proposed that toxin B is cleaved by a cytosolic factor of the eukaryotic target cell during its cellular uptake. Here we report that cleavage of not only toxin B, but also all other large clostridial cytotoxins, is an autocatalytic process dependent on host cytosolic inositolphosphate cofactors. A covalent inhibitor of aspartate proteases, 1,2-epoxy-3-(p-nitrophenoxy)propane, completely blocked toxin B function on cultured cells and was used to identify its catalytically active protease site. To our knowledge this is the first report on a bacterial toxin that uses eukaryotic signals for induced autoproteolysis to deliver its toxic domain into the cytosol of target cells. On the basis of our data, we present an integrated model for the uptake and inositolphosphate-induced activation of toxin B.