Processing of hemojuvelin requires retrograde trafficking to the Golgi in HepG2 cells.
Hemojuvelin (HJV) was recently identified as a critical regulator of iron homeostasis. It is either associated with cell membranes through a glycosylphosphatidylinositol anchor or released as a soluble form. Membrane-anchored HJV acts as a coreceptor for bone morphogenetic proteins and activates the transcription of hepcidin, a hormone that regulates iron efflux from cells. Soluble HJV antagonizes bone morphogenetic protein signaling and suppresses hepcidin expression. In this study, we examined the trafficking and processing of HJV. Cellular HJV reached the plasma membrane without obtaining complex oligosaccharides, indicating that HJV avoided Golgi processing. Secreted HJV, in contrast, has complex oligosaccharides and can be derived from HJV with high-mannose oligosaccharides at the plasma membrane. Our results support a model in which retrograde trafficking of HJV before cleavage is the predominant processing pathway. Release of HJV requires it to bind to the transmembrane receptor neogenin. Neogenin does not, however, play a role in HJV trafficking to the cell surface, suggesting that it could be involved either in retrograde trafficking of HJV or in cleavage leading to HJV release.
Maxson
Julia E
JE
Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, OR 97239, USA.
Enns
Caroline A
CA
Zhang
An-Sheng
AS
D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005372:Filipin / Q000494:pharmacology; D045683:Furin / Q000378:metabolism; D058851:GPI-Linked Proteins; D006031:Glycosylation; D006056:Golgi Apparatus / Q000502:physiology*; D000071020:Hemochromatosis Protein; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009844:Oligosaccharides / Q000378:metabolism; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000494:pharmacology; D021381:Protein Transport / Q000502:physiology*; D034741:RNA, Small Interfering
D058851:GPI-Linked Proteins; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; D008565:Membrane Proteins; D009844:Oligosaccharides; D034741:RNA, Small Interfering; C091279:neogenin; D005372:Filipin; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase; C468731:FURIN protein, human; D045683:Furin; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase