Copper overload impairs hematopoietic stem and progenitor cell proliferation via prompting HSF1/SP1 aggregation and the subsequently downregulating FOXM1-Cytoskeleton axis
LingYa Li,
ZhiPeng Tai,
WenYe Liu,
Yi Luo,
You Wu,
ShuHui Lin,
Mugen Liu,
BaoXiang Gao,
Jing-Xia Liu
Affiliations
LingYa Li
College of Fisheries, Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, Hubei 430070, China
ZhiPeng Tai
College of Fisheries, Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, Hubei 430070, China
WenYe Liu
College of Fisheries, Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, Hubei 430070, China
Yi Luo
College of Fisheries, Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, Hubei 430070, China
You Wu
College of Fisheries, Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, Hubei 430070, China
ShuHui Lin
College of Fisheries, Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, Hubei 430070, China
Mugen Liu
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
BaoXiang Gao
Key Laboratory of Analytical Science and Technology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding, Hebei 071002, China
Jing-Xia Liu
College of Fisheries, Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, Hubei 430070, China; Corresponding author
Summary: 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) via down-regulating expression of foxm1-cytoskeleton 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 HSF1 and SP1 on their downstream FOXM1 as well as the FOXM1 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.
