Journal Article

HSP70 sequestration by free α-globin promotes ineffective erythropoiesis in β-thalassaemia

Hazoume, Adonis, Baudin-Creuza, Véronique, Beuzard, Yves, de Beauchêne, Isaure Chauvot, Sevin, Margaux, Tchertanov, Luba, Guillem, Flavia, Moura, Ivan Cruz, Chretien, Stany, Garrido, Carmen, Hermine, Olivier, Maciel, Thiago Trovati, Arlet, Jean-Benoît, Belaid-Choucair, Zakia, Seigneuric, Renaud, Marcion, Guillaume, Courtois, Geneviève, Demarest, Samuel, Fontenay, Michaela, Dussiot, Michaël, Ribeil, Jean-Antoine, Negre, Olivier, Leboulch, Philippe, Auclair, Christian

2014

Overview

In human β-thalassaemiaerythroblasts, HSP70 is sequestered in the cytoplasm by the excess of free α-globin chains and can no longer protect the master transcriptional factor of erythropoiesis GATA-1 from caspase-3 cleavage; transduction of a nuclear-targeted HSP70 or a caspase-3 uncleavable GATA-1 mutant restored maturation of erythropoiesis. HSP70 a target in β-thalassemia During normal human erythroid cell maturation, the chaperone protein HSP70 translocates to the nucleus where it protects the master transcriptional factor of erythropoiesis, GATA1, from caspase-3 cleavage. Here Jean-Benoît Arlet et al . show that in erythroblasts from patients with the inherited haemoglobinopathy β-thalassemia major (β-TM), HSP70 is sequestered in the cytoplasm by the excess of free α-globin chains that accumulate in these cells. Transduction of a nuclear-targeted HSP70 mutant or a caspase-3-uncleavable GATA1 mutant restores maturation of β-TM erythroblasts. The discovery of a mechanism contributing to the ineffective erythropoiesis seen in β-TM suggests a rationale for possible targeted therapies for β-TM β-Thalassaemia major (β-TM) is an inherited haemoglobinopathy caused by a quantitative defect in the synthesis of β-globin chains of haemoglobin, leading to the accumulation of free α-globin chains that form toxic aggregates 1 , 2 . Despite extensive knowledge of the molecular defects causing β-TM, little is known of the mechanisms responsible for the ineffective erythropoiesis observed in the condition, which is characterized by accelerated erythroid differentiation, maturation arrest and apoptosis at the polychromatophilic stage 3 , 4 , 5 , 6 . We have previously demonstrated that normal human erythroid maturation requires a transient activation of caspase-3 at the later stages of maturation 7 . Although erythroid transcription factor GATA-1, the master transcriptional factor of erythropoiesis, is a caspase-3 target, it is not cleaved during erythroid differentiation. We have shown that, in human erythroblasts, the chaperone heat shock protein70 (HSP70) is constitutively expressed and, at later stages of maturation, translocates into the nucleus and protects GATA-1 from caspase-3 cleavage 8 . The primary role of this ubiquitous chaperone is to participate in the refolding of proteins denatured by cytoplasmic stress, thus preventing their aggregation 9 . Here we show in vitro that during the maturation of human β-TM erythroblasts, HSP70 interacts directly with free α-globin chains. As a consequence, HSP70 is sequestrated in the cytoplasm and GATA-1 is no longer protected, resulting in end-stage maturation arrest and apoptosis. Transduction of a nuclear-targeted HSP70 mutant or a caspase-3-uncleavable GATA-1 mutant restores terminal maturation of β-TM erythroblasts, which may provide a rationale for new targeted therapies of β-TM.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/1 / 13/106 / 13/109 / 13/2 / 13/21 / 13/31 / 13/51 / 14 / 14/1 / 14/19 / 692/699/1541/13 / 82 / 82/111 / 82/29 / 82/80 / 82/83 / alpha-Globins / alpha-Globins - metabolism / Apoptosis / beta-Thalassemia - blood / beta-Thalassemia - metabolism / beta-Thalassemia - pathology / beta-Thalassemia/blood/metabolism/pathology / Biochemistry, Molecular Biology / Bone Marrow - metabolism / Caspase 3 - metabolism / Cell Nucleus - metabolism / Cell Survival - genetics / Cells, Cultured / Cellular Biology / Cytoplasm - metabolism / EC 3.4.22.- (Caspase 3) / Enzyme Activation / Erythroblasts - cytology / Erythroblasts - metabolism / Erythroblasts - pathology / Erythroblasts/cytology/metabolism/pathology / Erythropoiesis - genetics / GATA1 protein, human / GATA1 Transcription Factor / GATA1 Transcription Factor - genetics / GATA1 Transcription Factor - metabolism / GATA1 Transcription Factor/genetics/metabolism / Gene Expression Regulation / Health aspects / Heat shock proteins / Hematology / Hemoglobin / HSP70 Heat-Shock Proteins / HSP70 Heat-Shock Proteins - genetics / HSP70 Heat-Shock Proteins - metabolism / HSP70 Heat-Shock Proteins/genetics/metabolism / Human health and pathology / Human health sciences / Humanities and Social Sciences / Humans / Hématologie / Kinetics / letter / Life Sciences / Molecular biology / Molecular Targeted Therapy / multidisciplinary / Physiological aspects / Protein Binding / Protein Refolding / Science / Sciences de la santé humaine / Subcellular Processes / Thalassemia