The precise regulation of the iron-regulatory hormone hepcidin is essential to maintain body iron homeostasis: Hepcidin deficiency induces iron overload, and hepcidin excess results in anaemia. Mutations in the gene HFE2 cause severe iron overload and are associated with low hepcidin expression. Recent data suggest that HFE2 is a bone morphogenetic protein (BMP) co-receptor, and that the decreased hepcidin mRNA expression because of HFE2 dysfunction is a result of impaired BMP signalling ability. In this study, we identify a critical BMP-responsive element (BMP-RE) at position -84/-79 of the hepcidin promoter. We show that this element mediates HFE2-dependent basal hepcidin mRNA expression under control conditions. Unexpectedly, the mutation of the same BMP-RE element also severely impairs hepcidin activation in response to IL-6. These data uncover a missing link in the HFE2-mediated control of hepcidin expression and suggest that the BMP-RE controls hepcidin promoter activity mediated by HFE2 and inflammatory stimuli.
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