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核SUMOylation和蛋白质毒性应激反应对具有不同连接物偏好的金属

Giorgiana Madalina Ursu¹, Casey Krawic¹, Anatoly Zhitkovich¹

¹Department of Pathology and Laboratory Medicine, Brown University, 70 Ship Street, Providence, Rhode Island 02903, United States.

Chemical research in toxicology

|April 17, 2025

概括

软金属和硬金属的电友会触发不同的细胞应激反应. 硬电友如 (III) 不能激活细胞质损伤传感器,而软金属如 (II) 不能.

科学领域:

细胞应激反应机制细胞应激反应机制
蛋白质毒性损伤途径的蛋白质毒性损伤途径
金属诱导的电友应力是金属引起的电友应力.

背景情况:

细胞拥有蛋白质毒性压力监测系统,主要由热冲击因子1 (HSF1) 和核因素红色素2相关因子2 (NRF2) 驱动.
这些系统利用软核友 (Cys-SH) 来感知电友损伤.
细胞对SH反应不良,硬电友的反应在很大程度上仍然没有表征.

研究的目的:

研究由具有不同电友软度的致癌金属诱导的明显蛋白毒性应激反应.
为了比较细胞对软 (Cd(II),中间 (Co(II) 和硬 (Cr(III)) 电友的反应.
阐明核SUMOylation在调解对金属诱导蛋白毒性反应中的作用.

主要方法:

暴露正常的人类肺细胞对 (II), (II) 和 (III) 等有毒剂量的暴露.
评估细胞和核应激反应,包括蛋白质无化和SUMOylation.
评估抗氧化剂亚斯科巴酸盐和PML对细胞反应的影响.
分析SUMOylation抑制对压力反应目标的转录和表达的影响.

主要成果:

软 (II) 强烈激活了细胞质NRF2和HSF1,诱导了多基化蛋白和中度ER/线粒体未折叠蛋白质反应.
硬 (III) 主要诱导核损伤和多SUMOylation,未能激活细胞质应激反应.
介质 ((II) 触发了一系列反应,激活HSF1和NRF2,但不激活细胞质聚比基聚合物.
在所有金属的核PML体中积聚了SUMOylated蛋白质,并且SUMOylation抑制损害了NRF2和HSF1目标基因表达.

结论:

软金属和硬金属的电友会引起不同的蛋白质毒性应激反应.
硬的电友,如 (III),不会激活细胞质损伤监测系统.
核SUMOylation在细胞质应激激活通路的功能中起着至关重要的作用,特别是在对金属电友的反应中.

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