A therapeutic chemical chaperone inhibits cholera intoxication and unfolding/translocation of the cholera toxin A1 subunit.
A therapeutic chemical chaperone inhibits cholera intoxication and unfolding/translocation of the cholera toxin A1 subunit.
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DOI：
10.1371/journal.pone.0018825
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发表时间：
2011-04-19
期刊：
影响因子：
3.7
通讯作者：
Teter K
中科院分区：
文献类型：
--
作者：
Taylor M;Banerjee T;Navarro-Garcia F;Huerta J;Massey S;Burlingame M;Pande AH;Tatulian SA;Teter K
霍乱毒素（CT）作为完整的AB 5蛋白毒素从细胞表面行进到中毒细胞的内质网（ER）。在ER中，催化A1亚基与毒素的其余部分分离。然后，通过ER相关降解（ERAD）的质量控制机制促进CTA 1从ER向胞质溶胶的转运。热不稳定性在分离的CTA 1亚基产生未折叠的毒素构象，作为ERAD介导的易位到胞质溶胶的触发器。在这项工作中，我们通过圆二色性和荧光光谱表明，暴露于4-苯基丁酸（PBA）抑制了CTA 1的热解折叠。这反过来又阻止了CTA 1的ER到胞质溶胶的出口和培养细胞或大鼠回肠袢的生产性中毒。在细胞培养研究中，PBA不影响CT运输到ER，CTA 1从全毒素解离，或ERAD系统的功能。PBA目前用作治疗尿素循环障碍的治疗剂。我们的数据表明PBA也可以用于预防或治疗霍乱的新应用。
Cholera toxin (CT) travels as an intact AB5 protein toxin from the cell surface to the endoplasmic reticulum (ER) of an intoxicated cell. In the ER, the catalytic A1 subunit dissociates from the rest of the toxin. Translocation of CTA1 from the ER to the cytosol is then facilitated by the quality control mechanism of ER-associated degradation (ERAD). Thermal instability in the isolated CTA1 subunit generates an unfolded toxin conformation that acts as the trigger for ERAD-mediated translocation to the cytosol. In this work, we show by circular dichroism and fluorescence spectroscopy that exposure to 4-phenylbutyric acid (PBA) inhibited the thermal unfolding of CTA1. This, in turn, blocked the ER-to-cytosol export of CTA1 and productive intoxication of either cultured cells or rat ileal loops. In cell culture studies PBA did not affect CT trafficking to the ER, CTA1 dissociation from the holotoxin, or functioning of the ERAD system. PBA is currently used as a therapeutic agent to treat urea cycle disorders. Our data suggest PBA could also be used in a new application to prevent or possibly treat cholera.
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