Wang Shunchang, Zhu Dandan, Wu Jingjing, Ma Yin, Wang Wenhui, Chu Zhaoxia, He Mei
School of Biological Engineering, Huainan Normal University, Huainan 232038, China; Key Laboratory of Bioresource and Environmental Biotechnology of Anhui Higher Education Institutes, Huainan Normal University, Huainan 232038, China.
School of Biological Engineering, Huainan Normal University, Huainan 232038, China; Key Laboratory of Bioresource and Environmental Biotechnology of Anhui Higher Education Institutes, Huainan Normal University, Huainan 232038, China.
Ecotoxicol Environ Saf. 2025 Sep 15;303:118880. doi: 10.1016/j.ecoenv.2025.118880. Epub 2025 Aug 21.
Cadmium exposure is a major public health concern. Understanding the mechanisms underlying cadmium resistance is crucial for developing preventive strategies and ecological remediation. However, the mechanisms underlying cadmium resistance in animal models remain poorly understood. In this study, we used the nematode Caenorhabditis elegans as a model and found that mild activation of the ER unfolded protein response (UPR) through tfg-1 RNAi promoted cadmium resistance, and excessive activation of the UPR resulted in inhibitory effects. Members of the canonical IRE-1/XBP-1 branch, ire-1 and xbp-1, are required for cadmium resistance. Worm strains that constitutively expressed the UPR reporter were cadmium-resistant, which was abrogated by xbp-1 RNAi. Activation of the UPR in the insulin/IGF-1 mutated strain daf-2(e1370) enhanced cadmium resistance. Cadmium resistance was abrogated in the daf-16(mu86) mutant strain under UPR; thus, DAF-16/FOXO bypassed UPR under cadmium exposure. Activation of UPR by tfg-1 RNAi stabilized the expression of tryptophan 5-monooxygenase and reduced the aggregation of toxic polyglutamine under cadmium exposure, whereas RNAi against xbp-1 exerted counteracting effects. Taken together, our results demonstrate that mild activation of UPR promotes cadmium resistance in C. elegans by maintaining protein homeostasis, and that xbp-1 plays a key role in mediating the process.
镉暴露是一个重大的公共卫生问题。了解镉抗性的潜在机制对于制定预防策略和生态修复至关重要。然而，动物模型中镉抗性的潜在机制仍知之甚少。在本研究中，我们以线虫秀丽隐杆线虫为模型，发现通过tfg-1 RNA干扰轻度激活内质网未折叠蛋白反应（UPR）可促进镉抗性，而过度激活UPR则产生抑制作用。经典的IRE-1/XBP-1分支成员ire-1和xbp-1是镉抗性所必需的。组成型表达UPR报告基因的线虫品系具有镉抗性，而xbp-1 RNA干扰可消除这种抗性。在胰岛素/胰岛素样生长因子-1突变株daf-2(e1370)中激活UPR可增强镉抗性。在UPR条件下，daf-16(mu86)突变株的镉抗性被消除；因此，DAF-16/FOXO在镉暴露条件下绕过了UPR。通过tfg-1 RNA干扰激活UPR可稳定色氨酸5-单加氧酶的表达，并减少镉暴露条件下有毒多聚谷氨酰胺的聚集，而针对xbp-1的RNA干扰则产生相反的效果。综上所述，我们的结果表明，轻度激活UPR通过维持蛋白质稳态促进秀丽隐杆线虫的镉抗性，并且xbp-1在介导这一过程中起关键作用。
