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J. Biol. Chem., Vol. 283, Issue 25, 17494-17502, June 20, 2008

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Neogenin-mediated Hemojuvelin Shedding Occurs after Hemojuvelin Traffics to the Plasma Membrane^*

An-Sheng Zhang¹, Fan Yang, Kathrin Meyer, Catalina Hernandez, Tara Chapman-Arvedson^¶, 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, ^¶Amgen, Thousand Oaks, California 91320, and the ^||Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California 91125

HFE2 (hemochromatosis type 2 gene) is highly expressed in skeletal muscle and liver hepatocytes. Its encoded protein, hemojuvelin (HJV), is a co-receptor for the bone morphogenetic proteins 2 and 4 (BMP2 and BMP4) and enhances the BMP-induced hepcidin expression. Hepcidin is a central iron regulatory hormone predominantly secreted from hepatocytes. HJV also binds neogenin, a membrane protein widely expressed in many tissues. Neogenin is required for the processing and release of HJV from cells. The role that neogenin plays in HJV trafficking was investigated, using HepG2 cells, a human hepatoma cell line. Knockdown of endogenous neogenin markedly suppresses HJV release but has no evident effect on HJV trafficking to the plasma membrane. The addition of a soluble neogenin ectodomain to cells markedly inhibits HJV release, indicating that the HJV shedding is not processed before trafficking to the cell surface. At the plasma membrane it undergoes endocytosis in a dynamin-independent but cholesterol-dependent manner. The additional findings that HJV release is coupled to lysosomal degradation of neogenin and that cholesterol depletion by filipin blocks both HJV endocytosis and HJV release suggest that neogenin-mediated HJV release occurs after the HJV-neogenin complex is internalized from the cell surface.

Received for publication, December 26, 2007 , and in revised form, April 29, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK080765 (to A.-S. Z.) and DK54488 (to C. A. E.). This work was also supported by funds from Amgen (to A.-S. Z.). 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.

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

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