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Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plamsa membrane

Zhang, An-Sheng and Yang, Fan and Meyer, Kathrin and Hernandez, Catalina and Chapman-Arvedson, Tara and Bjorkman, Pamela J. and Enns, Caroline A. (2008) Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plamsa membrane. Journal of Biological Chemistry, 283 (25). pp. 17494-17502. ISSN 0021-9258. PMCID PMC2427329.

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Hemochromatosis type 2 gene (HFE2) 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. 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, that HJV undergoes endocytosis, 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.

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Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2008 the American Society for Biochemistry and Molecular Biology. Submitted on December 26, 2007. Revised on April 29, 2008. Accepted on April 29, 2008. Papers In Press, published online ahead of print April 29, 2008. We would like to thank Julia Maxson, Maja Chloupkova, Juxing Chen and Junwei Gao in Caroline Enns’ lab for critical reading of the manuscript and valuable comments. 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.
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Issue or Number:25
PubMed Central ID:PMC2427329
Record Number:CaltechAUTHORS:ZHAjbc08
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ID Code:10343
Deposited By: Archive Administrator
Deposited On:30 Apr 2008
Last Modified:03 Oct 2019 00:08

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