Submitted August 15, 2008
Accepted November 11, 2008
Processing of hemojuvelin requires retrograde trafficking to the Golgi in HepG2 cells
Julia E Maxson, Caroline A Enns, and An-Sheng Zhang*
Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, OR, United States
* Corresponding author; email: zhanga{at}ohsu.edu.
Hemojuvelin (HJV) was recently identified as a critical regulator of iron homeostasis. It is either associated with cell membranes through a GPI-anchor or released as a soluble form. Membrane anchored HJV 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. 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 oligosaccharies at the plasma membrane. Our results support a model in which retrograde trafficking of HJV prior to 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.
