Matriptase-2-mediated suppression of hepatic hepcidin expression in mice requires hepatocyte neogenin

Neogenin (NEO1) is a ubiquitously expressed multifunctional receptor. It binds members of the repulsive guidance molecules (RGM), RGMa, RGMb, and hemojuvelin (HJV). While RGMa and RGMb binding to NEO1 are necessary for neural development, more recent studies demonstrated that the Neo1-Hjv interaction in hepatocytes plays a pivotal role in iron homeostasis by facilitating hepcidin expression through the bone morphogenetic protein (BMP)-signaling pathway. Hepcidin is an iron regulatory hormone. In mice, ablation of Neo1 or Hjv reduces hepcidin and causes iron overload. Similar effects occur upon disruption of the Neo1-Hjv association. Besides HJV, NEO1 also interacts with matriptase-2 (MT2), a key suppressor for hepcidin expression. MT2 mutations result in an inappropriately high hepcidin and iron-refractory iron-deficiency anemia in humans. MT2 is a membrane-anchored serine protease. It can cleave multiple components of the hepcidin induction pathway in vitro, including HJV. In this study, we investigated the roles of Neo1-Mt2 interaction in hepcidin expression in vivo. In contrast to the observations that Mt2 cleaves Neo1 and markedly reduces Neo1 levels in cultured hepatoma cells, we found that Mt2 stabilizes Neo1 in murine liver. Studies in mice suggest that Mt2 suppression of hepcidin relies on the presence of Neo1. Additional investigations imply that the major function of hepatic Neo1 is to set the basal levels of hepcidin expression. Together, these data along with the evidence that Mt2 also suppresses the function of Hjv, support the model that Mt2 suppression of hepatic hepcidin is achieved by inhibiting the Neo1/Hjv-induced Bmp-signaling pathway.