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J. Biol. Chem., Vol. 280, Issue 40, 33885-33894, October 7, 2005

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Interaction of Hemojuvelin with Neogenin Results in Iron Accumulation in Human Embryonic Kidney 293 Cells^*

An-Sheng Zhang1, Anthony P. West, Jr., Anne E. Wyman, Pamela J. Bjorkman¶, and Caroline A. Enns

From the Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon 97239, the Division of Biology, California Institute of Technology, Pasadena, California 91125, and the ^¶Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California 91125

Type 2 hereditary hemochromatosis (HH) or juvenile hemochromatosis is an early onset, genetically heterogeneous, autosomal recessive disorder of iron overload. Type 2A HH is caused by mutations in the recently cloned hemojuvelin gene (HJV; also called HFE2) (Papanikolaou, G., Samuels, M. E., Ludwig, E. H., MacDonald, M. L., Franchini, P. L., Dube, M. P., Andres, L., MacFarlane, J., Sakellaropoulos, N., Politou, M., Nemeth, E., Thompson, J., Risler, J. K., Zaborowska, C., Babakaiff, R., Radomski, C. C., Pape, T. D., Davidas, O., Christakis, J., Brissot, P., Lockitch, G., Ganz, T., Hayden, M. R., and Goldberg, Y. P. (2004) Nat. Genet. 36, 77–82), whereas Type 2B HH is caused by mutations in hepcidin. HJV is highly expressed in both skeletal muscle and liver. Mutations in HJV are implicated in the majority of diagnosed juvenile hemochromatosis patients. In this study, we stably transfected HJV cDNA into human embryonic kidney 293 cells and characterized the processing of HJV and its effect on iron homeostasis. Our results indicate that HJV is a glycosylphosphatidylinositol-linked protein and undergoes a partial autocatalytic cleavage during its intracellular processing. HJV co-immunoprecipitated with neogenin, a receptor involved in a variety of cellular signaling processes. It did not interact with the closely related receptor DCC (deleted in Colon Cancer). In addition, the HJV G320V mutant implicated in Type 2A HH did not co-immunoprecipitate with neogenin. Immunoblot analysis of ferritin levels and transferrin-⁵⁵Fe accumulation studies indicated that the HJV-induced increase in intracellular iron levels in human embryonic kidney 293 cells is dependent on the presence of neogenin in the cells, thus linking these two proteins to intracellular iron homeostasis.

Received for publication, June 7, 2005 , and in revised form, July 28, 2005.

^* This work was supported by National Institutes of Health Grants DK54488 (to C. A. E.) and R01 DK60770 (to P. J. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental figures.

¹ To whom correspondence should be addressed: Dept. of Cell and Developmental Biology, L215, Oregon Health & Science University, 3181 SW Sam Jackson Park Blvd., Portland, OR 97239. Tel.: 503-494-5846; Fax: 503-494-4253; E-mail: zhanga{at}ohsu.edu.

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