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Complex biosynthesis of RGMc/Hemojuvelin, a Muscle‐Enriched Regulator of Systemic Iron Metabolism
Author(s) -
Kuninger David Thomas,
Kuns Robin,
Kuzmickas Ryan,
Rotwein Peter
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a106-b
Subject(s) - hepcidin , skeletal muscle , regulator , glycosylation , hemochromatosis , biology , microbiology and biotechnology , gene , biochemistry , protein biosynthesis , hereditary hemochromatosis , endoplasmic reticulum , chemistry , endocrinology , genetics , immunology , inflammation
The recently discovered repulsive guidance molecule c gene (RGMc; also known as HJV) encodes a putative glycosylphosphatidylinositol (GPI)‐anchored protein that is expressed predominately in skeletal muscle and to lesser degree in the heart and liver. Mutations in the RGMc gene have been linked to the most common form of juvenile hemochromatosis, a severe iron overloading disorder. Loss of RGMc has been correlated with decreased hepatic production of hepcidin, a critical regulator of iron homeostasis. Here we show that RGMc gene activation and protein synthesis occurs early during muscle cell differentiation. We also provide evidence that RGMc is produced as a single transcript in muscle cells, and that the resulting protein can undergo complex processing to generate distinctly modified pools of both membrane‐attached and secreted RGMc. At the plasma membrane of muscle cells, endogenous RGMc exists predominately as an internally cleaved GPI‐anchored protein whose polypeptides remain intact via intra‐molecular disulfide bonds. RGMc is also secreted by muscle cells. The two secreted forms are both intact proteins with a conserved NH 2 ‐terminus, but may differ in the extent of glycosylation or through a COOH‐terminal truncation. Our results provide an experimental framework for establishing mechanisms of regulation and action of muscle‐derived RGMc in whole body iron metabolism, and for understanding the biochemical basis of juvenile hemochromatosis.