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

The Mediterranean region under climate change

This book has been published by Allenvi (French National Alliance for Environmental Research) to coincide with the 22nd Conference of Parties to the United Nations Framework Convention on Climate Change (COP22) in Marrakesh. It is the outcome of work by academic researchers on both sides of the Mediterranean and provides a remarkable scientific review of the mechanisms of climate change and its impacts on the environment, the economy, health and Mediterranean societies. It will also be valuable in developing responses that draw on “scientific evidence” to address the issues of adaptation, resource conservation, solutions and risk prevention. Reflecting the full complexity of the Mediterranean environment, the book is a major scientific contribution to the climate issue, where various scientific considerations converge to break down the boundaries between disciplines