Oxidative Stress and 𝜷-Thalassemic Erythroid Cells behind the Molecular Defect

Figure 2

Schematic model of novel cytoprotective mechanisms in response to oxidative stress in β-thalassemic (β-thal) erythroid precursors. In β-thalassemic erythropoiesis the radical oxidative species (ROS) induces peroxiredoxin-2 (PRDX2) expression. In the early stage of β-thalassemic erythropoiesis, ROS and heme levels are both increased and PRDX2 acts on both targets; in more mature cells, when ROS levels are still high and heme levels are reduced, ROS might become the PRDX2 major target (see text for details). ROS promotes HRI activation, which requires the heat shock proteins 70 and 90 (HSP70,-90). HRI activation results in phosphorylation of the α-subunit of eIF2, an important regulatory translation initiating factor, which inhibits the α-, β-globin chain synthesis and activates the Atf4 pathway towards redox genes such as heme-oxygenase-1 (ho-1), glutathione S-transferase (gst), and NAD(P)H quinone oxidoreductase 1 (Nqo1). The upregulation of these genes in combination with the decrease in α-, β-globin chain synthesis might beneficially affect the ineffective erythropoiesis of β-thalassemia. The α chains (AHSP, α hemoglobin-stabilizing protein) is another cytoprotective system, which partially protects the erythroid precursors from the α chain excess. AHSP binds free α-globin chains, stabilizing their structure. AHSP prevents their precipitation and might be important in β-thalassemic erythropoiesis characterized by unbalance in globin chain synthesis.