Hemojuvelin-neogenin interaction is required for bone morphogenic protein-4-induced hepcidin expression

J Biol Chem. 2009 Aug 21;284(34):22580-9. doi: 10.1074/jbc.M109.027318. Epub 2009 Jun 29.


Hemojuvelin (HJV) is a glycosylphosphatidylinositol-linked protein and binds both bone morphogenic proteins (BMPs) and neogenin. Cellular HJV acts as a BMP co-receptor to enhance the transcription of hepcidin, a key iron regulatory hormone secreted predominantly by liver hepatocytes. In this study we characterized the role of neogenin in HJV-regulated hepcidin expression. Both HJV and neogenin were expressed in liver hepatocytes. Knockdown of neogenin decreased BMP4-induced hepcidin mRNA levels by 16-fold in HJV-expressing HepG2 cells but only by about 2-fold in cells transfected with either empty vector or G99V mutant HJV that does not bind BMPs. Further studies indicated that disruption of the HJV-neogenin interaction is responsible for a marked suppression of hepcidin expression. Moreover, in vivo studies showed that hepatic hepcidin mRNA could be significantly suppressed by blocking the interaction of HJV with full-length neogenin with a soluble fragment of neogenin in mice. Together, these results suggest that the HJV-neogenin interaction is required for the BMP-mediated induction of hepcidin expression when HJV is expressed. Combined with our previous studies, our results support that hepatic neogenin possesses two functions, mediation of cellular HJV release, and stimulation of HJV-enhanced hepcidin expression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / genetics*
  • Blotting, Western
  • Bone Morphogenetic Protein 4 / metabolism*
  • Bone Morphogenetic Protein 4 / pharmacology
  • Cell Line, Tumor
  • Cells, Cultured
  • GPI-Linked Proteins
  • Gene Expression Regulation* / drug effects
  • Hemochromatosis Protein
  • Hepatocytes / metabolism
  • Hepcidins
  • Humans
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Membrane Proteins / pharmacology
  • Mice
  • Mutagenesis, Site-Directed
  • RNA, Small Interfering
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction


  • Antimicrobial Cationic Peptides
  • Bone Morphogenetic Protein 4
  • GPI-Linked Proteins
  • HAMP protein, human
  • HJV protein, human
  • Hamp protein, mouse
  • Hamp protein, rat
  • Hemochromatosis Protein
  • Hepcidins
  • Hjv protein, rat
  • Membrane Proteins
  • RNA, Small Interfering
  • neogenin