The mechanism by which the TfR2/HFE complex affects iron homeostasis

• DOI: 10.1096/fasebj.27.1_supplement.835.12
• Publication Date: 2021-06-16T10:17:34Z
• Authors: Christal Anna Wor...; Maja Chloupková; Ken Noguchi; Caroline A Enns
• Keywords: 0303 health sciences; 03 medical and health sciences; 3. Good health

Iron homeostasis is tightly controlled. Since there is no regulated way of excreting excess iron, levels are finely tuned through dietary uptake. This is mostly accomplished by the peptide hormone, hepcidin, which is produced in the liver and regulated by the BMP‐signaling pathway. The hereditary hemochromatosis protein (HFE) and transferrin receptor 2 (TfR2) form a complex and regulate the BMP‐signaling pathway in response to blood transferrin‐bound iron levels. Mutations in either protein result in a reduction in BMP signaling and hepcidin expression, leading to iron overload. How the TfR2/HFE complex affects BMP signaling is unknown. The purpose of this study was to determine the mechanism by which TfR2 and HFE affect BMP‐signaling and iron homeostasis. We found that TfR2 and the BMP co‐receptor, hemojuvelin, interact through immunoprecipitation, and that HFE stabilizes this interaction. This establishes an important link between the iron‐sensing TfR2/HFE complex and BMP signaling. To further understand how this complex affects BMP signaling, we created mutant forms of TfR2 and HFE and studied them in vitro, using minicircle DNA technology in primary hepatocytes, and in vivo, using adeno‐associated virus under the control of a liver‐specific promoter.NIH RO1 DK054488T32 5T32GM071338–08