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

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