Receptor-specific requirements for anthrax toxin delivery into cells
Receptor-specific requirements for anthrax toxin delivery into cells
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DOI：
10.1073/pnas.0505865102
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发表时间：
2005-09-13
影响因子：
11.1
通讯作者：
Young, JAT
中科院分区：
文献类型：
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作者：
Rainey, GJA;Wigelsworth, DJ;Young, JAT
构成炭疽毒素的三种蛋白质在其中一种蛋白质（保护性抗原（PA））结合肿瘤内皮标志物8（TEM 8）或毛细血管形态发生蛋白2（CMG 2）细胞受体后自组装成毒性复合物。毒素受体复合物被内化，酸性内体pH通过PA触发孔形成并将催化亚基易位到胞质溶胶中。在这项研究中，我们表明，PA prepore的孔和易位的转化的pH阈值不同，约一个pH值单位，这取决于是否使用TEM 8或CMG2受体。对于TEM8相关毒素，这些事件可以在接近中性pH值时发生，并且它们对细胞中的氯化铵处理显示出相对低的敏感性。相比之下，对于CMG 2相关毒素，这些事件需要更酸性的条件，并且对氯化铵高度敏感。此外，我们表明，PA从TEM8和CMG2孔形成时解离。我们的研究结果是一致的模型，其中易位取决于孔的形成和孔的形成，反过来，取决于PA从其受体的释放。我们提出，由于PA与CMG2的结合亲和力比与TEM 8的结合亲和力高得多，因此需要较低的pH来减弱CMG2结合以允许孔形成。我们的研究结果表明，毒素可以形成孔在不同点的内吞途径，这取决于受体用于进入。
The three proteins that constitute anthrax toxin self -assemble into toxic complexes after one of these proteins, protective antigen (PA), binds to tumor endothelial marker 8 (TEM8) or capillary morphogenesis protein 2 (CMG2) cellular receptors. The toxin receptor complexes are internalized, and acidic endosomal pH triggers pore formation by PA and translocation of the catalytic subunits into the cytosol. In this study we show that the pH threshold for conversion of the PA prepore to the pore and for translocation differs by approximately a pH unit, depending on whether the TEM8 or CMG2 receptor is used. For TEM8-associated toxin, these events can occur at close to neutral pH values, and they show relatively low sensitivity to ammonium chloride treatment in cells. In contrast, with CMG2-associated toxin, these events require more acidic conditions and are highly sensitive to ammonium chloride. We show, furthermore, that PA dissociates from TEM8 and CMG2 upon pore formation. Our results are consistent with a model in which translocation depends on pore formation and pore formation, in turn, depends on release of PA from its receptor. We propose that because PA binds to CMG2 with much higher affinity than it does to TEM8, a lower pH is needed to attenuate CMG2 binding to allow pore formation. Our results suggest that toxin can form pores at different points in the endocytic pathway, depending on which receptor is used for entry.