EDAG mediates Hsp70 nuclear localization in erythroblasts and rescues dyserythropoiesis in myelodysplastic syndrome.
Apoptosis
/ physiology
Caspase 3
/ metabolism
Cell Differentiation
/ physiology
Cell Nucleus
/ metabolism
Cells, Cultured
Cytoplasm
/ metabolism
Erythroblasts
/ metabolism
Erythropoiesis
/ physiology
Gene Expression Regulation
/ physiology
HSP70 Heat-Shock Proteins
/ metabolism
Hematologic Diseases
/ metabolism
Humans
Myelodysplastic Syndromes
/ metabolism
Nuclear Proteins
/ metabolism
EDAG
Hsp70
dyserythropoiesis
myelodysplastic syndrome
nuclear localization
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
26
11
2019
revised:
06
04
2020
accepted:
13
04
2020
pubmed:
1
5
2020
medline:
16
1
2021
entrez:
1
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32350948
doi: 10.1096/fj.201902946R
doi:
Substances chimiques
HEMGN protein, human
0
HSP70 Heat-Shock Proteins
0
Nuclear Proteins
0
Caspase 3
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8416-8427Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
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