Hemojuvelin (HJV) was recently identified as a critical regulator of iron homeostasis. It is either associated with the cells through a GPI-anchor or released as a soluble form. The cellular form acts as a co-receptor for bone morphogenic proteins (BMPs) and activates the transcription of hepcidin, a hormone that regulates iron efflux from cells. Soluble HJV antagonizes BMP signaling and suppresses hepcidin expression. Secretion of HJV requires binding to the transmembrane receptor neogenin. 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, had complex oligosaccharides and could be derived from the pool of HJV at the plasma membrane. Neogenin did not play a role in HJV trafficking to the cell surface but was necessary for secretion of HJV, suggesting that it could be involved in either retrograde trafficking of HJV or in cleavage leading to secretion.

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