Alternative RNA Splicing Generates a Glycosylphosphatidylinositol-anchored Form of Ceruloplasmin in Mammalian Brain
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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.
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In hepatocytes derived from HIF-1α-knockout mice, hepcidin expression in response to iron deficiency was increased.
“in hepatocytes derived from HIF-1α-knockout mice, hepcidin expression in response to iron deficiency was increased (242).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [242]
HIF-1α binds to TfR1 HRE.
“HIF-1α was shown to bind to TfR1 HRE.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [242]
Hepatocytes and liver samples from mice with deleted VHL were iron deficient and showed increased expression of Fpn.
“hepatocytes and liver samples from mice with deleted von Hip-pel-Lindau (VHL), which is the negative regulator of HIF-1, were iron deficient and showed increased expression of Fpn (Fig. 7) (242).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [242]
HIF-1 has been implicated in the transcriptional regulation of hepcidin in response to hypoxia.
“HIF-1 has been implicated in the transcriptional regulation of hepcidin in response to hypoxia (242).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [242]
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- Authors
- Patel, B. N., Dunn, R. J., & David, S.
- Affiliations
- Montreal General Hospital (CA)
- Corresponding author
- David, Samuel
- ORCID
- David, Samuel
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-02
- Volume
- 275
- Issue
- 6
- Pages
- 4305-4310
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2057172958
- Cited by
- 202
- References
- 37
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 11 · 2018: 9 · 2017: 6 · 2016: 6 · 2015: 8 · 2014: 10 · 2013: 8 · 2012: 4
- FWCI
- 5.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- ceruloplasmin, alternative splicing, glycosylphosphatidylinositol anchoring, brain, astrocytes, aceruloplasminemia, iron homeostasis, iron accumulation, neurodegeneration, liver
- MeSH terms
- Amino Acid Sequence, Animals, Brain, Cell Line, Ceruloplasmin, Cloning, Molecular, Humans, Immunohistochemistry, Iron, Liver, Membrane Proteins, Molecular Sequence Data, Type C Phospholipases, Ribonucleases, RNA, Messenger, Transfection, Gene Expression, Sequence Alignment, Glycosylphosphatidylinositols, Alternative Splicing, Phosphatidylinositol Diacylglycerol-Lyase
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