Abstract
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.
Highlights
Iron plays an important role in many biological processes
Ceruloplasmin is generally considered a plasma protein secreted by the liver, we recently demonstrated that a membrane-bound glycosylphosphatidylinositol (GPI)-anchored form of ceruloplasmin is localized to the surface of astrocytes in the central nervous system (CNS) [9]
Since a lack of ceruloplasmin leads to excessive iron deposition in the brain and neurodegeneration, the GPI-anchored form of ceruloplasmin likely plays a crucial role in iron metabolism in the CNS
Summary
Iron plays an important role in many biological processes. It is an essential cofactor for a variety of enzymes, including ribonucleotide reductase and aconitase, and its presence in heme imparts the ability of hemoglobin to transport oxygen and the ability of cytochrome oxidase to reduce oxygen to water. Ceruloplasmin is generally considered a plasma protein secreted by the liver, we recently demonstrated that a membrane-bound glycosylphosphatidylinositol (GPI)-anchored form of ceruloplasmin is localized to the surface of astrocytes in the CNS [9]. This report describes the cloning and expression of a novel alternatively spliced transcript for the GPI-anchored form of ceruloplasmin.
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