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首页> 外文期刊>Frontiers in Cellular and Infection Microbiology >Overexpression of the Endosomal Anion/Proton Exchanger ClC-5 Increases Cell Susceptibility toward Clostridium difficile Toxins TcdA and TcdB
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Overexpression of the Endosomal Anion/Proton Exchanger ClC-5 Increases Cell Susceptibility toward Clostridium difficile Toxins TcdA and TcdB

机译：内体阴离子/质子交换子ClC-5的过表达增加了细胞对艰难梭菌毒素TcdA和TcdB的敏感性

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Virulent C. difficile toxins TcdA and TcdB invade host intestinal epithelia by endocytosis and use the acidic environment of intracellular vesicles for further processing and activation. We investigated the role of ClC-5, a chloride/proton exchanger expressed in the endosomes of gastrointestinal epithelial cells, in the activation and processing of C. difficile toxins. Enhanced intoxication by TcdA and TcdB was observed in cells expressing ClC-5 but not ClC-4, another chloride/proton exchanger with similar function but different localization. In accordance with the established physiological function of ClC-5, its expression lowered the endosomal pH in HEK293T cells by ~0.6 units and enhanced ~five-fold the internalization of TcdA. In colon HT29 cells, 34% of internalized TcdA localized to ClC-5-containing vesicles defined by colocalization with Rab5, Rab4a, and Rab7 as early and early-to-late of endosomes but not as Rab11-containing recycling endosomes. Impairing the cellular uptake of TcdA by deleting the toxin CROPs domain did not abolish the effects of ClC-5. In addition, the transport-incompetent mutant ClC-5 E268Q similarly enhanced both endosomal acidification and intoxication by TcdA but facilitated the internalization of the toxin to a lower extent. These data suggest that ClC-5 enhances the cytotoxic action of C. difficile toxins by accelerating the acidification and maturation of vesicles of the early and early-to-late endosomal system. The dispensable role of electrogenic ion transport suggests that the voltage-dependent nonlinear capacitances of mammalian CLC transporters serve important physiological functions. Our data shed light on the intersection between the endocytotic cascade of host epithelial cells and the internalization pathway of the large virulence C. difficile toxins. Identifying ClC-5 as a potential specific host ion transporter hijacked by toxins produced by pathogenic bacteria widens the horizon of possibilities for novel therapies of life-threatening gastrointestinal infections.
机译：艰难梭菌毒素TcdA和TcdB通过内吞作用侵入宿主肠道上皮，并利用细胞内囊泡的酸性环境进行进一步加工和激活。我们研究了ClC-5（在胃肠道上皮细胞的内体中表达的氯化物/质子交换剂）在艰难梭菌毒素的激活和加工中的作用。在表达ClC-5但不表达ClC-4的细胞中观察到TcdA和TcdB增强的中毒作用，ClC-4是另一种具有相似功能但定位不同的氯化物/质子交换剂。根据已建立的ClC-5的生理功能，其表达将HEK293T细胞中的内体pH降低了约0.6个单位，并使TcdA的内在化程度提高了约五倍。在结肠HT29细胞中，34％的内在TcdA局部化为含ClC-5的囊泡，通过与Rab5，Rab4a和Rab7共定位为内体的早期和晚期，而不是含Rab11的回收内体。通过删除毒素CROPs结构域损害TcdA的细胞摄取并没有消除ClC-5的作用。此外，运输能力不佳的突变体ClC-5 E268Q同样增强了TcdA的内体酸化和中毒作用，但在较低程度上促进了毒素的内在化。这些数据表明，ClC-5通过加速早期和晚期晚期内体系统囊泡的酸化和成熟来增强艰难梭菌毒素的细胞毒性作用。电离子迁移的不可或缺的作用表明，哺乳动物CLC转运蛋白的电压依赖性非线性电容具有重要的生理功能。我们的数据揭示了宿主上皮细胞的内吞级联与大毒力艰难梭菌毒素的内在途径之间的相交。将ClC-5鉴定为潜在的特定宿主离子转运蛋白，其被致病细菌产生的毒素劫持，为威胁生命的胃肠道感染的新疗法开辟了广阔的前景。

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