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Published August 21, 2009 | Published + Supplemental Material
Journal Article Open

Hemojuvelin-Neogenin Interaction Is Required for Bone Morphogenic Protein-4-induced Hepcidin Expression

Abstract

Hemojuvelin (HJV) is a glycosylphosphatidylinositol-linked protein and binds both bone morphogenic proteins (BMPs) and neogenin. Cellular HJV acts as a BMP co-receptor to enhance the transcription of hepcidin, a key iron regulatory hormone secreted predominantly by liver hepatocytes. In this study we characterized the role of neogenin in HJV-regulated hepcidin expression. Both HJV and neogenin were expressed in liver hepatocytes. Knockdown of neogenin decreased BMP4-induced hepcidin mRNA levels by 16-fold in HJV-expressing HepG2 cells but only by about 2-fold in cells transfected with either empty vector or G99V mutant HJV that does not bind BMPs. Further studies indicated that disruption of the HJV-neogenin interaction is responsible for a marked suppression of hepcidin expression. Moreover, in vivo studies showed that hepatic hepcidin mRNA could be significantly suppressed by blocking the interaction of HJV with full-length neogenin with a soluble fragment of neogenin in mice. Together, these results suggest that the HJV-neogenin interaction is required for the BMP-mediated induction of hepcidin expression when HJV is expressed. Combined with our previous studies, our results support that hepatic neogenin possesses two functions, mediation of cellular HJV release, and stimulation of HJV-enhanced hepcidin expression.

Additional Information

© 2009 the American Society for Biochemistry and Molecular Biology. Received for publication, February 19, 2009 , and in revised form, June 4, 2009. Originally published In Press as doi:10.1074/jbc.M109.027318 on June 29, 2009. We thank Dr. Pamela Bjorkman at Caltech for generously providing us with the neogenin FNIII 5–6 fragment and the neogenin ectodomain, Dr. Gregory Longmore at Washington University for generously giving us tTA-HepG2 cells and a tetracycline-inducible pcDNA4 plasmid, and Julia Maxson, Maja Chloupkova, Gary Reiness, Juxing Cheng, Junwei Gao, and Kristina Nicholson for critical reading of this manuscript and helpful comments. This work was supported, in whole or in part, by National Institutes of Health Grants DK080765 (to A.-S. Z.), P50AA11199 (to H. T.), and R24AA12885 (to H. T.). The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3.

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Published - Zhang2009p5782Journal_of_Biological_Chemistry.pdf

Supplemental Material - Zhang1.pdf

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