The Serine Protease Matriptase-2 (TMPRSS6) Inhibits Hepcidin Activation by Cleaving Membrane Hemojuvelin
Open accessAbstract
The liver peptide hepcidin regulates body iron, is upregulated in iron overload and inflammation, and is downregulated in iron deficiency/hypoxia. The transmembrane serine protease matriptase-2 (TMPRSS6) inhibits the hepcidin response and its mutational inactivation causes iron-deficient anemia in mice and humans. Here we confirm the inhibitory effect of matriptase-2 on hepcidin promoter; we show that matriptase-2 lacking the serine protease domain, identified in the anemic Mask mouse (matriptase-2(MASK)), is fully inactive and that mutant R774C found in patients with genetic iron deficiency has decreased inhibitory activity. Matriptase-2 cleaves hemojuvelin (HJV), a regulator of hepcidin, on plasma membrane; matriptase-2(MASK) shows no cleavage activity and the human mutant only partial cleavage capacity. Matriptase-2 interacts with HJV through the ectodomain since the interaction is conserved in matriptase-2(MASK). The expression of matriptase-2 mutants in zebrafish results in anemia, confirming the matriptase-2 role in iron metabolism and its interaction with HJV.
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The most powerful inhibitor is the liver transmembrane serine protease matriptase 2, encoded by TMPRSS6, which cleaves the BMP co-receptor hemojuvelin, thereby attenuating BMP-SMAD signaling and hepcidin transcription.
“The most powerful inhibitor is the liver transmembrane serine protease matriptase 2, encoded by TMPRSS6,48 which cleaves the BMP co-receptor hemojuvelin,49 thereby attenuating BMP-SMAD signaling and hepcidin transcription.”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [49]
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- Authors
- Silvestri, L., Pagani, A., Nai, A., De Domenico, I., Kaplan, J., & Camaschella, C.
- Affiliations
- Vita-Salute San Raffaele University (IT)
- University of Utah (US)
- Corresponding author
- Camaschella, Clara
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2008-12
- Volume
- 8
- Issue
- 6
- Pages
- 502-511
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC2648389
- OpenAlex
- W2012956876
- Cited by
- 555
- References
- 9
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 12 · 2023: 23 · 2022: 26 · 2021: 27 · 2020: 19 · 2019: 32 · 2018: 27 · 2017: 36 · 2016: 32 · 2015: 29 · 2014: 35 · 2013: 41 · 2012: 47
- FWCI
- 30.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Fondazione Telethon
- National Institute of Diabetes and Digestive and Kidney Diseases (DK070947, R01DK070947)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- matriptase-2, TMPRSS6, hepcidin, hemojuvelin, serine protease, iron metabolism, iron deficiency anemia, zebrafish, proteolytic cleavage
- MeSH terms
- Hemochromatosis Protein, Animals, Cell Membrane, Cells, Cultured, Endoplasmic Reticulum, HeLa Cells, Humans, Membrane Proteins, Promoter Regions, Genetic, Protein Processing, Post-Translational, Serine Endopeptidases, Zebrafish, Signal Transduction, Amino Acid Substitution, Antimicrobial Cationic Peptides, GPI-Linked Proteins, Hepcidins
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