Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plasma membrane

An-Sheng Zhang, Fan Yang, Kathrin Meyer, Catalina Hernandez, Tara Chapman-Arvedson, Pamela J. Bjorkman, Caroline Enns

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

HFE2 (hemochromatosis type 2 gene) is highly expressed in skeletal muscle and liver hepatocytes. Its encoded protein, hemojuvelin (HJV), is a co-receptor for the bone morphogenetic proteins 2 and 4 (BMP2 and BMP4) and enhances the BMP-induced hepcidin expression. Hepcidin is a central iron regulatory hormone predominantly secreted from hepatocytes. HJV also binds neogenin, a membrane protein widely expressed in many tissues. Neogenin is required for the processing and release of HJV from cells. The role that neogenin plays in HJV trafficking was investigated, using HepG2 cells, a human hepatoma cell line. Knockdown of endogenous neogenin markedly suppresses HJV release but has no evident effect on HJV trafficking to the plasma membrane. The addition of a soluble neogenin ectodomain to cells markedly inhibits HJV release, indicating that the HJV shedding is not processed before trafficking to the cell surface. At the plasma membrane it undergoes endocytosis in a dynamin-independent but cholesterol-dependent manner. The additional findings that HJV release is coupled to lysosomal degradation of neogenin and that cholesterol depletion by filipin blocks both HJV endocytosis and HJV release suggest that neogenin-mediated HJV release occurs after the HJV-neogenin complex is internalized from the cell surface.

Original languageEnglish (US)
Pages (from-to)17494-17502
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number25
DOIs
StatePublished - Jun 20 2008

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Cell membranes
Cell Membrane
Hepcidins
Endocytosis
Hepatocytes
Cholesterol
Filipin
Bone Morphogenetic Protein 4
Dynamins
Bone Morphogenetic Protein 2
neogenin
Hep G2 Cells
Liver
Muscle
Hepatocellular Carcinoma
Membrane Proteins
Skeletal Muscle
Iron
Genes
Cells

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plasma membrane. / Zhang, An-Sheng; Yang, Fan; Meyer, Kathrin; Hernandez, Catalina; Chapman-Arvedson, Tara; Bjorkman, Pamela J.; Enns, Caroline.

In: Journal of Biological Chemistry, Vol. 283, No. 25, 20.06.2008, p. 17494-17502.

Research output: Contribution to journalArticle

Zhang, An-Sheng ; Yang, Fan ; Meyer, Kathrin ; Hernandez, Catalina ; Chapman-Arvedson, Tara ; Bjorkman, Pamela J. ; Enns, Caroline. / Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plasma membrane. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 25. pp. 17494-17502.
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