Li LingYa, Tai ZhiPeng, Liu WenYe, Luo Yi, Wu You, Lin ShuHui, Liu Mugen, Gao BaoXiang, Liu Jing-Xia
College of Fisheries, Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
iScience. 2023 Mar 14;26(4):106406. doi: 10.1016/j.isci.2023.106406. eCollection 2023 Apr 21.
Unbalanced Cu homeostasis has been suggested to be associated with hematopoietic disease, but the roles of Cu overload in the hematopoietic system and the potential mechanisms are obscure. Here, we report a novel association and the novel potential pathways for Cu overload to induce proliferation defects in zebrafish embryonic hematopoietic stem and progenitor cells (HSPCs) down-regulating expression of - axis, which is conserved from fish to mammals. Mechanistically, we show the direct binding of Cu to transcriptional factors HSF1 and SP1 and that Cu overload induces the cytoplasmic aggregation of proteins HSF1 and SP1. These result in the reduced transcriptional activities of and on their downstream as well as the transcriptional activities on cytoskeletons in HSPCs, which leads to ultimately cell proliferation impairment. These findings unveil the novel linkage of Cu overload with specific signaling transduction as well as the subsequent HSPC proliferation defects.
不平衡的铜稳态被认为与造血系统疾病有关，但铜过载在造血系统中的作用及其潜在机制尚不清楚。在此，我们报告了一种新的关联以及铜过载诱导斑马鱼胚胎造血干细胞和祖细胞（HSPCs）增殖缺陷的新潜在途径，该途径通过下调从鱼类到哺乳动物都保守的 - 轴的表达来实现。从机制上讲，我们展示了铜与转录因子HSF1和SP1的直接结合，并且铜过载诱导蛋白质HSF1和SP1的细胞质聚集。这些导致HSF1和SP1对其下游基因的转录活性降低，以及对HSPCs细胞骨架的转录活性降低，最终导致细胞增殖受损。这些发现揭示了铜过载与特定信号转导以及随后的HSPC增殖缺陷之间的新联系。
