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EDAG mediates Hsp70 nuclear localization in erythroblasts and rescues dyserythropoiesis in myelodysplastic syndrome
Author(s) -
Dong XiaoMing,
Zhao Ke,
Zheng WeiWei,
Xu ChengWang,
Zhang MeiJiang,
Yin RongHua,
Gao Rui,
Tang Liujun,
Liu JinFang,
Chen Hui,
Zhan YiQun,
Yu Miao,
Ge ChangHui,
Gao HuiYing,
Li Xiu,
Luo Teng,
Ning HongMei,
Yang XiaoMing,
Li ChangYan
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902946r
Subject(s) - microbiology and biotechnology , haematopoiesis , hsp70 , cytoplasm , nucleus , nuclear localization sequence , chromosomal translocation , nuclear export signal , biology , cell nucleus , apoptosis , heat shock protein , stem cell , gene , genetics
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.