Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Ulm, Germany.
Munich Center for Integrated Protein Science and Department Chemistry, Technical University of Munich, Munich, Germany.
Sci Rep. 2017 Apr 4;7(1):613. doi: 10.1038/s41598-017-00780-x.
Diphtheria toxin kills human cells because it delivers its enzyme domain DTA into their cytosol where it inhibits protein synthesis. After receptor-mediated uptake of the toxin, DTA translocates from acidic endosomes into the cytosol, which might be assisted by host cell factors. Here we investigated the role of Hsp90 and its co-chaperones during the uptake of native diphtheria toxin into human cells and identified the components of the Hsp90 machinery including Hsp90, Hsp70, Cyp40 and the FK506 binding proteins FKBP51 and FKBP52 as DTA binding partners. Moreover, pharmacological inhibition of the chaperone activity of Hsp90 and Hsp70 and of the peptidyl-prolyl cis/trans isomerase (PPIase) activity of Cyps and FKBPs protected cells from intoxication with diphtheria toxin and inhibited the pH-dependent trans-membrane transport of DTA into the cytosol. In conclusion, these host cell factors facilitate toxin uptake into human cells, which might lead to development of novel therapeutic strategies against diphtheria.
白喉毒素通过将其酶结构域 DTA 递送至细胞质中抑制蛋白质合成从而杀死人类细胞。在毒素受体介导的摄取后，DTA 从酸性内体易位至细胞质中，这可能受到宿主细胞因子的辅助。在此，我们研究了热休克蛋白 90（Hsp90）及其共伴侣在天然白喉毒素进入人类细胞摄取过程中的作用，并鉴定了 Hsp90 机器的组成部分，包括 Hsp90、Hsp70、Cyp40 以及 FK506 结合蛋白 FKBP51 和 FKBP52，它们都是 DTA 的结合伴侣。此外，Hsp90 和 Hsp70 的伴侣活性以及 Cyp 和 FKBP 的肽基脯氨酰顺反异构酶（PPIase）活性的药理学抑制可保护细胞免受白喉毒素的中毒，并抑制 DTA 在细胞质中的 pH 依赖性跨膜转运。总之，这些宿主细胞因子促进了毒素进入人类细胞，这可能为白喉的新型治疗策略的发展提供了思路。
