Original Article

Journal of Molecular Medicine

, Volume 87, Issue 5, pp 471-480

Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV/BMP/SMAD

  • Guillem CasanovasAffiliated withDepartment of Pediatric Oncology, Hematology and Immunology, University of HeidelbergMolecular Medicine Partnership Unit, European Molecular Biology Laboratory
  • , Katarzyna Mleczko-SaneckaAffiliated withDepartment of Pediatric Oncology, Hematology and Immunology, University of HeidelbergMolecular Medicine Partnership Unit, European Molecular Biology LaboratoryEuropean Molecular Biology Laboratory
  • , Sandro AltamuraAffiliated withDepartment of Pediatric Oncology, Hematology and Immunology, University of HeidelbergMolecular Medicine Partnership Unit, European Molecular Biology LaboratoryEuropean Molecular Biology Laboratory
  • , Matthias W. HentzeAffiliated withMolecular Medicine Partnership Unit, European Molecular Biology LaboratoryEuropean Molecular Biology Laboratory
  • , Martina U. MuckenthalerAffiliated withDepartment of Pediatric Oncology, Hematology and Immunology, University of HeidelbergMolecular Medicine Partnership Unit, European Molecular Biology Laboratory Email author 

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Abstract

The hemochromatosis proteins HFE, transferrin receptor 2 (TfR2) and hemojuvelin (HJV, HFE2) positively control expression of the major iron regulatory hormone hepcidin. HJV is a bone morphogenetic protein (BMP) co-receptor that enhances the cellular response to BMP cytokines via the phosphorylation of SMAD proteins. In this study, we show that two highly conserved and sequence-identical BMP-responsive elements located at positions −84/−79 (BMP-RE1) and −2,255/−2,250 (BMP-RE2) of the human hepcidin promoter are critical for both the basal hepcidin mRNA expression and the hepcidin response to BMP-2 and BMP-6. While BMP-RE1 and BMP-RE2 show additive effects in responding to HJV-mediated BMP signals, only BMP-RE1 that is located in close proximity to a previously identified STAT-binding site is important for the hepcidin response to IL-6. These data identify a missing link between the HJV/BMP signaling pathways and hepcidin transcription, and further define the connection between inflammation and BMP-dependent hepcidin promoter activation. As such, they provide important new information furthering our understanding of disorders of iron metabolism and the anemia of inflammation.

Keywords

Hereditary hemochromatosis Hemojuvelin SMAD Anemia of inflammation IL-6