Graduate Institute of Biomedical Sciences, Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan.
Department of Physiology, School of Medicine, China Medical University, Taichung, Taiwan.
J Microbiol Immunol Infect. 2024 Oct;57(5):709-719. doi: 10.1016/j.jmii.2024.07.007. Epub 2024 Aug 3.
Cytolethal distending toxin (CDT) belongs to the genotoxin family and is closely related to Campylobacter jejuni-associated gastroenteritis. We recently reported that CDT triggers the danger-associated molecular pattern (DAMP) signaling to exert deleterious effects on host cells. However, how CDT traffics in cells and the mechanism of CDT intoxication remain to be elucidated.
Recombinant CDT subunits (CdtA, CdtB, and CdtC) were purified, and their activity was characterized in gastrointestinal cells. Molecular approaches and image tracking were employed to analyze the delivery of CDT in host cells.
In this study, we found that CDT interacts with the receptor of advanced glycation end products (RAGE) and high mobility group box 1 (HMGB1) to enter the cells. Our results further showed that CdtB transport in cells through the dynamin-dependent endocytic pathway and lysosome is involved in this process. Conversely, blockage of RAGE signaling resulted in a reduction in CDT-arrested cell cycles, indicating that RAGE is involved in CDT intracellular transport and its subsequent pathogenesis.
Our results demonstrate that RAGE is important for CDT trafficking in the cells. These findings expand our understanding of important issues related to host cell intoxication by C. jejuni CDT.
细胞致死膨胀毒素（CDT）属于遗传毒素家族，与空肠弯曲菌相关的胃肠炎密切相关。我们最近报道 CDT 触发危险相关分子模式（DAMP）信号，对宿主细胞产生有害影响。然而，CDT 在细胞内如何运输以及 CDT 中毒的机制仍有待阐明。
纯化重组 CDT 亚基（CdtA、CdtB 和 CdtC），并在胃肠道细胞中表征其活性。采用分子方法和图像跟踪分析 CDT 在宿主细胞中的传递。
在这项研究中，我们发现 CDT 与晚期糖基化终产物（RAGE）和高迁移率族蛋白 B1（HMGB1）的受体相互作用进入细胞。我们的结果进一步表明，CdtB 通过依赖于胞吞作用的内吞途径和溶酶体在细胞内运输，这一过程涉及其中。相反，阻断 RAGE 信号会导致 CDT 阻止的细胞周期减少，表明 RAGE 参与 CDT 细胞内运输及其随后的发病机制。
我们的结果表明，RAGE 对于 CDT 在细胞内的运输很重要。这些发现扩展了我们对空肠弯曲菌 CDT 引起宿主细胞中毒的重要问题的理解。
