Autocatalytic cleavage of Clostridium difficile toxin B

摘要

Clostridium difficile是在医院中发生的感染的原因。它见于一些健康 成年人的大肠中，正是由于在抗生素治疗过程中“好的”肠道细菌数 量的减少，才为C. difficile毒素引起严重腹泻和大肠炎创造了条件。 一项新的研究表明，所有大型梭菌类细胞毒素的分解是一个自催化过 程，也就是说该毒素激发其本身，是由宿主纤维醇磷酸酯共因子诱导 的。C. difficile!感染极难治疗，所以将治疗药物瞄准这一由毒素激发 的分解过程具有潜在重要性。%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.