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首页> 外文期刊>Infection and immunity >Mutant Escherichia coli Heat-Labile Toxin B Subunit That Separates Toxoid-Mediated Signaling and Immunomodulatory Action from Trafficking and Delivery Functions
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Mutant Escherichia coli Heat-Labile Toxin B Subunit That Separates Toxoid-Mediated Signaling and Immunomodulatory Action from Trafficking and Delivery Functions

机译：突变的大肠杆菌热不稳定毒素B亚基，将类毒素介导的信号传导和免疫调节作用与贩运和传递功能分开

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The homopentameric B-subunit components of Escherichia coli heat-labile enterotoxin (EtxB) and cholera toxin (CtxB) possess the capacity to enter mammalian cells and to activate cell-signaling events in leukocytes that modulate immune cell function. Both properties have been attributed to the ability of the B subunits to bind to GM1-ganglioside receptors, a ubiquitous glycosphingolipid found in the plasma membrane. Here we describe the properties of EtxB(H57S), a mutant B subunit with a His→Ser substitution at position 57. The mutant was found to be severely defective in inducing leukocyte signaling, as shown by failure to (i) trigger caspase 3-mediated CD8+-T-cell apoptosis, (ii) activate nuclear translocation of NF-κB in Jurkat T cells, (iii) induce a potent anti-B-subunit response in mice, or (iv) serve as a mucosal adjuvant. However, its GM1 binding, cellular uptake, and delivery functions remained intact. This was further validated by the finding that EtxB(H57S) was as effective as EtxB in delivering a conjugated model class I epitope into the major histocompatibility complex class I pathway of a dendritic cell line. These observations imply that GM1 binding alone is not sufficient to trigger the signaling events responsible for the potent immunomodulatory properties of EtxB. Moreover, they demonstrate that its signaling properties play no role in EtxB uptake and trafficking. Thus, EtxB(H57S) represents a novel tool for evaluating the complex cellular interactions and signaling events occurring after receptor interaction, as well as offering an alternative means of delivering attached peptides in the absence of the potent immunomodulatory signals induced by wild-type B subunits.
机译：大肠杆菌热不稳定肠毒素（EtxB）和霍乱毒素（CtxB）的同五聚体B亚基组分具有进入哺乳动物细胞的能力，并激活白细胞中的细胞信号转导事件，从而调节免疫细胞的功能。这两个特性都归因于B亚基与GM1-神经节苷脂受体（质膜中普遍存在的糖鞘脂）结合的能力。在这里，我们描述了EtxB（H57S）的特性，EtxB（H57S）是突变B的亚基，在位置57处有His→Ser取代。发现该突变体在诱导白细胞信号传导方面存在严重缺陷，如未能成功（i）触发caspase 3-介导的CD8 + -T细胞凋亡，（ii）激活Jurkat T细胞中NF-κB的核易位，（iii）在小鼠中诱导有效的抗B亚基应答，或（iv）充当粘膜佐剂。但是，其GM1绑定，细胞摄取和传递功能保持不变。通过发现EtxB（H57S）与EtxB一样有效，可将共轭的I类模型表位递送至树突状细胞系的主要组织相容性复合物I类途径中，这一点进一步证实了这一点。这些观察结果表明，单独的GM1结合不足以触发负责EtxB有效免疫调节特性的信号传递事件。此外，他们证明了其信号传导特性在EtxB摄取和运输中不起作用。因此，EtxB（H57S）代表了一种新颖的工具，可用于评估复杂的细胞相互作用和受体相互作用后发生的信号传导事件，并提供了一种在缺少野生型B亚基诱导的有效免疫调节信号的情况下递送附着肽的替代方法。

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