Transferrin receptor 1: Keeper of HFE

In this issue of Blood, Xiao et al(1) demonstrate that the hemochromatosis protein HFE is required for the participation of hepatocellular transferrin receptor 1 (TFR1) in the co-regulation of iron metabolism and erythropoiesis. Such co-regulation is essential to maintain iron homeostasis and normal red blood cell production, and its disruption contributes to the pathology of the iron-loading anemias and multiple conditions of erythropoietin resistance. Hepatocytes couple iron availability to iron demand by sensing extracellular signals reflective of erythropoietic activity (erythroferrone [ERFE]), iron utili-zation (iron-bound transferrin [FeTF]), and liver iron stores (bone morphoge-netic proteins [BMP6/2]) to influence hepcidin production. Hepcidin then regulates the release of iron into the circulation from sites of storage and from the diet to TF for utilization, primarily in hemoglobin production. Identified hepatocellular sensors of these extracellular signals include the BMP receptor complex and the 2 transferrin receptors (TFR1 and TFR2). Identification of the individual and interrelated contributions of these "iron sensors" has provided insights into novel therapeutic approaches to correct their dysregulation.