Regulatory Role of Transferrin in Erythropoiesis and Iron Metabolism

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ABSTRACT The overall goal of our proposal is to investigate how iron metabolism and erythropoietic activity are interrelated, and the mechanisms whereby dysregulation in one contributes to pathophysiology in the other. Roles for the two transferrin receptors in these processes is clear; however, little is understood regarding the signaling properties of their ligand, transferrin. Transferrin has long been recognized to deliver iron by binding to receptor, transferrin receptor 1 (TFR1), present on all cells. More recently, a homologous receptor, TFR2, has been identified almost exclusively on bone marrow and liver cells where it serves as a sensor of iron supply and a regulator of erythropoiesis. We generated mice in which one or other of the two iron binding sites (N and C) was mutated, and unable to take in iron. We observed striking differences in the regulation of iron metabolism and erythropoiesis between these mice, demonstrating that each of lobes of transferrin has distinct signaling properties. We present in this proposal new data demonstrating significant improvement in a mouse model of the human disease β-thalassemia when iron is specifically bound to the N but not C lobe. We now devote our attention to the mechanisms by which the two transferrin lobes exert their effects. We also explore the potential of increasing N lobe TF as a potential treatment approach in ineffective erythropoiesis.