Arsenic pollution in drinking water is a widespread public health problem, and it affects approximately 200 million people in over 70 countries. Many human diseases, including neurodegenerative disorders, are engendered by the malfunction of proteins involved in important biological processes and are elicited by protein misfolding and/or loss of protein quality control during translation. Arsenic exposure results in proteotoxic stress, though the detailed molecular mechanisms remain poorly understood. Here, we showed that arsenite interacts with ZNF598 protein in cells and exposure of human skin fibroblasts to arsenite results in significant decreases in the ubiquitination levels of lysine residues 138 and 139 in RPS10 and lysine 8 in RPS20, which are regulatory post-translational modifications important in ribosome-associated protein quality control. Furthermore, the arsenite-elicited diminutions in ubiquitinations of RPS10 and RPS20 gave rise to augmented read-through of poly(adenosine)-containing stalling sequences, which was abolished in ZNF598 knockout cells. Together, our study revealed a novel mechanism underlying the arsenic-induced proteostatic stress in human cells.

中文翻译：

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砷与ZNF598结合，干扰了核糖体相关蛋白的质量控制。

饮用水中的砷污染是普遍存在的公共卫生问题，它影响了70多个国家的大约2亿人。许多人类疾病，包括神经退行性疾病，是由参与重要生物学过程的蛋白质功能失常引起的，并且是由蛋白质错误折叠和/或翻译过程中蛋白质质量控​​制的丧失引起的。砷暴露会引起蛋白毒性应激，尽管对其详细的分子机制仍知之甚少。在这里，我们发现亚砷酸盐与细胞中的ZNF598蛋白相互作用，人皮肤成纤维细胞暴露于亚砷酸盐会导致RPS10中的赖氨酸残基138和139和RPS20中的赖氨酸8的泛素化水平显着降低，它们是核糖体相关蛋白质量控制中重要的调控翻译后修饰。此外，由砷引起的RPS10和RPS20泛素化作用的减少导致含多腺苷的失速序列的通透性增强，而ZNF598敲除细胞中该序列被取消。总之，我们的研究揭示了一种潜在的机制，该机制是砷诱导的人体细胞蛋白水解应激的基础。