Hemojuvelin-neogenin interaction is required for bone morphogenic protein-4-induced hepcidin expression.
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.
Zhang
An-Sheng
AS
Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, USA. zhanga@ohsu.edu
Yang
Fan
F
Wang
Jiaohong
J
Tsukamoto
Hidekazu
H
Enns
Caroline A
CA
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D000071020:Hemochromatosis Protein; D022781:Hepatocytes / Q000378:metabolism; D064451:Hepcidins; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D034741:RNA, Small Interfering; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D023181:Antimicrobial Cationic Peptides; D055415:Bone Morphogenetic Protein 4; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C481006:HJV protein, human; C579599:Hamp protein, mouse; C578703:Hamp protein, rat; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C513726:Hjv protein, rat; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C091279:neogenin