Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin
Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin
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DOI：
10.1074/jbc.m608788200
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发表时间：
2007-04-27
影响因子：
4.8
通讯作者：
Enns, Caroline A.
中科院分区：
文献类型：
--
作者：
Zhang, An-Sheng;Anderson, Sheila A.;Enns, Caroline A.
由基因HFE 2编码的血幼素（HJV）是铁调素表达的关键上游调节剂。铁调素是一种中枢铁调节激素，由肝细胞分泌，而HFE 2在骨骼肌和肝脏中高度表达。先前的研究表明，HJV是一种GPI锚定蛋白，结合蛋白再生蛋白和骨形态发生蛋白（BMP 2和BMP 4），并可以从细胞膜释放（脱落）。在这项研究中，我们研究了HJV脱落的生理意义和潜在机制。在急性缺铁大鼠肝hepcidin的表达明显抑制，我们检测到早期阶段的血清HJV的增加，无论是HFE2的mRNA或蛋白水平在腓肠肌没有显着变化。在C2C12（小鼠成肌细胞系）和HepG2（人肝癌细胞系）细胞中的研究均显示出活跃的HJV脱落，这意味着骨骼肌和肝脏都可能是血清HJV的来源。与铁缺乏大鼠的观察结果一致，HJV脱落在这些细胞系中下调全转铁蛋白以浓度依赖性的方式。我们目前的研究表明，敲低内源性再生蛋白，HJV受体，在C2C12细胞抑制HJV脱落和再生蛋白在HEK293细胞中的过度表达显着增强这一过程，表明膜HJV脱落是由再生蛋白介导的。BMP 4及其拮抗剂noggin均不能改变HJV脱落，这一发现支持BMP信号通路在此过程中缺乏参与。
Hemojuvelin ( HJV), encoded by the gene HFE2, is a critical upstream regulator of hepcidin expression. Hepcidin, the central iron regulatory hormone, is secreted from hepatocytes, whereas HFE2 is highly expressed in skeletal muscle and liver. Previous studies demonstrated that HJV is a GPI-anchored protein, binds the proteins neogenin and bone morphogenetic proteins ( BMP2 and BMP4), and can be released from the cell membrane ( shedding). In this study, we investigated the physiological significance and the underlying mechanism of HJV shedding. In acutely iron-deficient rats with markedly suppressed hepatic hepcidin expression, we detected an early phase increase of serum HJV with no significant change of either HFE2 mRNA or protein levels in gastrocnemius muscle. Studies in both C2C12 ( a mouse myoblast cell line) and HepG2 ( a human hepatoma cell line) cells showed active HJV shedding, implying that both skeletal muscle and liver could be the source of serum HJV. In agreement with the observations in iron-deficient rats, HJV shedding in these cell lines was down-regulated by holo-transferrin in a concentration-dependent manner. Our present study showing that knockdown of endogenous neogenin, a HJV receptor, in C2C12 cells suppresses HJV shedding and that overexpression of neogenin in HEK293 cells markedly enhances this process, suggests that membrane HJV shedding is mediated by neogenin. The finding that neither BMP4 nor its antagonist, noggin, was able to alter HJV shedding support the lack of involvement of BMP signaling pathway in this process.