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

International audienceβ-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. 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. We have previously demonstrated that normal human erythroid maturation requires a transient activation of caspase-3 at the later stages of maturation. 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. The primary role of this ubiquitous chaperone is to participate in the refolding of proteins denatured by cytoplasmic stress, thus preventing their aggregation. 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-T

Preliminary evaluation of some aspects of the ecology (growth pattern, condition factor and reproductive biology) of African pike, Hepsetus odoe (Bloch 1794), in Lake Eleiyele, Ibadan, Nigeria

Abstract A preliminary investigation of length-weight relationship, condition factor and reproductive ecology of African pike fish, Hepsetus odoe, was conducted between June to August 2010 in Lake Eleiyele. A total of 90 samples of the fish species were caught by fishermen using gill nets. The results obtained showed that fish species had isometric growth pattern (contrary to negative allometry expected) with the growth exponent, b value of 2.64, that is not statistically different from 3 and with high statistical power of 0.866 when tested. The mean condition factor, K, was found to be 2.6, indicating that the fish species were in good condition in the study area. For reproductive biology, mean fecundity and gonadosomatic index were found to be 1349 eggs and 3.53% respectively. This study was necessary to fill the knowledge gap and provide information for management and conservation of the investigated species in the lake system. This study recommended that further research needs to be conducted because the sampling was carried out in the rainy season period and within a quarter of a year