EDAG mediates Hsp70 nuclear localization in erythroblasts and rescues dyserythropoiesis in myelodysplastic syndrome.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2020 Jun

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During human erythroid maturation, Hsp70 translocates into the nucleus and protects GATA-1 from caspase-3 cleavage. Failure of Hsp70 to localize to the nucleus was found in Myelodysplastic syndrome (MDS) erythroblasts and can induce dyserythropoiesis, with arrest of maturation and death of erythroblasts. However, the mechanism of the nuclear trafficking of Hsp70 in erythroblasts remains unknown. Here, we found the hematopoietic transcriptional regulator, EDAG, to be a novel binding partner of Hsp70 that forms a protein complex with Hsp70 and GATA-1 during human normal erythroid differentiation. EDAG overexpression blocked the cytoplasmic translocation of Hsp70 induced by EPO deprivation, inhibited GATA-1 degradation, thereby promoting erythroid maturation in an Hsp70-dependent manner. Furthermore, in myelodysplastic syndrome (MDS) patients with dyserythropoiesis, EDAG is dramatically down-regulated, and forced expression of EDAG has been found to restore the localization of Hsp70 in the nucleus and elevate the protein level of GATA-1 to a significant extent. In addition, EDAG rescued the dyserythropoiesis of MDS patients by increasing erythroid differentiation and decreasing cell apoptosis. This study demonstrates the molecular mechanism of Hsp70 nuclear sustaining during erythroid maturation and establishes that EDAG might be a suitable therapeutic target for dyserythropoiesis in MDS patients. © 2020 Federation of American Societies for Experimental Biology.

Citation

Xiao-Ming Dong, Ke Zhao, Wei-Wei Zheng, Cheng-Wang Xu, Mei-Jiang Zhang, Rong-Hua Yin, Rui Gao, Liu-Jun Tang, Jin-Fang Liu, Hui Chen, Yi-Qun Zhan, Miao Yu, Chang-Hui Ge, Hui-Ying Gao, Xiu Li, Teng Luo, Hong-Mei Ning, Xiao-Ming Yang, Chang-Yan Li. EDAG mediates Hsp70 nuclear localization in erythroblasts and rescues dyserythropoiesis in myelodysplastic syndrome. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020 Jun;34(6):8416-8427