title: Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression.
abstract: Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia. Mutations in the gene encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low hepcidin levels, suggesting that hemojuvelin positively regulates hepcidin expression. Hemojuvelin is a member of the repulsive guidance molecule (RGM) family, which also includes the bone morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Here, we report that hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability. Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2-/- hepatocytes. Our data suggest a mechanism by which HFE2 mutations cause hemochromatosis: hemojuvelin dysfunction decreases BMP signaling, thereby lowering hepcidin expression.
authors.affiliation: Program in Membrane Biology and Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Babitt
authors.forename: Franklin W
authors.initials: FW
authors.lastname: Huang
authors.forename: Diedra M
authors.initials: DM
authors.lastname: Wrighting
authors.forename: Yin
authors.initials: Y
authors.lastname: Xia
authors.forename: Yisrael
authors.initials: Y
authors.lastname: Sidis
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Samad
authors.forename: Jason A
authors.initials: JA
authors.lastname: Campagna
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.forename: Alan L
authors.initials: AL
authors.lastname: Schneyer
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Andrews
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Lin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation / Q000502:physiology*; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D023181:Antimicrobial Cationic Peptides; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D008565:Membrane Proteins; D016212:Transforming Growth Factor beta