Alternative RNA splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brain
Alternative RNA splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brain
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DOI：
10.1074/jbc.275.6.4305
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发表时间：
2000-02-11
影响因子：
4.8
通讯作者：
David, S
中科院分区：
文献类型：
--
作者：
Patel, BN;Dunn, RJ;David, S
铜蓝蛋白是一种含铜的亚铁氧化酶，对于正常的铁稳态至关重要。血浆中的铜蓝蛋白是由肝细胞产生和分泌的，而在大脑中，糖基磷脂酰肌醇（GPI）锚定形式的铜蓝蛋白表达在星形胶质细胞的表面。通过使用cDNA克隆方法，我们现在已经确定，GPI锚定形式的铜蓝蛋白是通过选择性RNA剪接产生的。剪接发生在外显子 18 的下游，并将分泌形式的 C 端 5 个氨基酸替换为另外 30 个氨基酸，这些氨基酸表示 GPI 锚定添加。 RNase 保护分析表明，GPI 锚定形式是大脑中的主要形式，而分泌形式在肝脏中占主导地位。患有铜蓝蛋白血症（一种遗传性铜蓝蛋白缺乏症）的个体在许多器官（包括大脑）中存在严重的铁沉积，从而导致神经变性。因此，这种新型 GPI 锚定形式的铜蓝蛋白可能在中枢神经系统铁代谢中发挥重要作用。
Ceruloplasmin is a copper containing ferroxidase that is essential for normal iron homeostasis. Whereas ceruloplasmin in plasma is produced and secreted by hepatocytes, in the brain a glycosylphosphatidylinositol (GPI)-anchored form of ceruloplasmin is expressed on the surface of astrocytes, By using a cDNA cloning approach, we have now determined that the GPI-anchored form of ceruloplasmin is generated by alternative RNA splicing. The splicing occurs downstream of exon 18 and replaces the C-terminal 5 amino acids of the secreted form with an alternative 30 amino acids that signal GPI anchor addition. RNase protection analysis demonstrates that the GPI-anchored form is the major form in the brain, whereas the secreted form predominates in the liver. Individuals with aceruloplasminemia, a hereditary deficiency of ceruloplasmin, have severe iron deposition in a number of organs, including the brain where it results-in neurodegeneration. Therefore, this novel GPI-anchored form of ceruloplasmin is likely to play an important role in iron metabolism in the central nervous system.