Defective targeting of hemojuvelin to plasma membrane is a common pathogenetic mechanism in juvenile hemochromatosis
Abstract
Hemojuvelin (HJV) positively modulates the iron regulator hepcidin, and its mutations are the major cause of juvenile hemochromatosis (JH), a recessive disease leading to iron overload. Defective HJV reduces hepcidin up-regulation both in humans and in Hjv-deficient mice. To investigate the JH pathogenesis and the functional properties of human HJV we studied the biosynthesis and maturation of 6 HJV pathogenic mutants in HeLa and HepG2 cells. We show that proteolytic processing is defective in mutants F170S, W191C, and G320V, but not in G99V and C119F. Moreover, we show that mutants G99V and C119F are targeted to the cell surface, while F170S, W191C, G320V, and R326X (lacking the glycosilphosphatidylinositol [GPI] anchor) are mainly retained in the endoplasmic reticulum, although all mutants are released as soluble forms (s-HJV) in a proportion that is modulated by iron supplementation. Membrane HJV (m-HJV) is mainly composed of the cleaved protein, and its level is increased by iron in wild-type (WT) mice but not in the mutants. Altogether, the data demonstrate that the loss of HJV membrane export is central to the pathogenesis of JH, and that HJV cleavage is essential for the export. The results support a dual function for s- and m-HJV in iron deficiency and overload, respectively.
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FRDA patient cells showed higher sensitivity to H2O2 toxicity in a ubiquitously distributed iron-dependent manner.
“although FRDA patient cells showed higher sensitivity to H2O2 toxicity in a ubiquitously distributed iron-dependent manner (283).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [283]
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Intracellular iron transport and storage: from molecular mechanisms to health implications
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- Authors
- Silvestri, L., Pagani, A., Fazi, C., Gerardi, G., Levi, S., Arosio, P., & Camaschella, C.
- Affiliations
- San Raffaele Scientific Institute, Dibit, Milan, Italy;
- Vita-Salute San Raffaele University (IT)
- University of Brescia (IT)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2007-01-30
- Volume
- 109
- Issue
- 10
- Pages
- 4503-4510
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W1966408698
- Cited by
- 84
- References
- 29
- Citations by year
- 2024: 2 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 5 · 2016: 5 · 2015: 4 · 2014: 3 · 2013: 8 · 2012: 2
- FWCI
- 7.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- Fondazione Telethon
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- hemojuvelin, juvenile hemochromatosis, hepcidin, iron overload, proteolytic cleavage, proteolytic processing, plasma membrane targeting, endoplasmic reticulum retention, glycosylphosphatidylinositol anchor, iron supplementation, iron deficiency, pathogenic variants
- MeSH terms
- Hemochromatosis Protein, Cell Membrane, Child, Endoplasmic Reticulum, HeLa Cells, Hemochromatosis, Humans, Iron, Membrane Proteins, Protein Processing, Post-Translational, Tumor Cells, Cultured, Protein Transport, Mutant Proteins, GPI-Linked Proteins
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