https://ror.org/02z2dfb58 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
https://ror.org/02z2dfb58 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
Life Sci Alliance. 2024 Nov 22;8(2). doi: 10.26508/lsa.202402866. Print 2025 Feb.
Non-essential metals are extremely toxic to living organisms, posing significant health risks, particularly in developing nations where they are a major contributor to illness and death. Although their toxicity is widely acknowledged, the mechanisms by which they are regulated within human cells remain incompletely understood. Specifically, the role of membrane transporters in mediating heavy metal toxicity is not well comprehended. Our study demonstrates how specific transporters can modulate the toxicity of cadmium, mercury, and the metalloid arsenic in human cells. Using CRISPR/Cas9 loss-of-function screens, we found that the multidrug resistance protein MRP1/ABCC1 provided protection against toxicity induced by arsenic and mercury. In addition, we found that SLC39A14 and SLC30A1 increased cellular sensitivity to cadmium. Using a reporter cell line to monitor cellular metal accumulation and performing a cDNA gain-of-function screen, we were able to clarify the function of SLC30A1 in controlling cadmium toxicity through the modulation of intracellular zinc levels. This transporter-wide approach provides new insights into the complex roles of membrane transporters in influencing the toxicity of arsenic, cadmium, and mercury in human cell lines.
非必需金属对生物体具有极强的毒性，会对健康造成重大风险，特别是在发展中国家，它们是导致疾病和死亡的主要因素。尽管它们的毒性已被广泛认识，但它们在人类细胞内的调节机制仍不完全清楚。具体来说，膜转运蛋白在介导重金属毒性方面的作用还没有被很好地理解。我们的研究表明，特定的转运蛋白如何调节人类细胞中镉、汞和类金属砷的毒性。通过使用 CRISPR/Cas9 基因敲除功能筛选，我们发现多药耐药蛋白 MRP1/ABCC1 为砷和汞诱导的毒性提供了保护。此外，我们发现 SLC39A14 和 SLC30A1 增加了细胞对镉的敏感性。我们使用报告细胞系监测细胞内金属积累，并进行 cDNA 功能获得筛选，从而阐明 SLC30A1 通过调节细胞内锌水平来控制镉毒性的功能。这种全转运蛋白方法为理解膜转运蛋白在影响人类细胞系中砷、镉和汞的毒性方面的复杂作用提供了新的见解。
