PUBLICATION
The Serine Protease Matriptase-2 (TMPRSS6) Inhibits Hepcidin Activation by Cleaving Membrane Hemojuvelin
- Authors
- Silvestri, L., Pagani, A., Nai, A., De Domenico, I., Kaplan, J., and Camaschella, C.
- ID
- ZDB-PUB-081105-8
- Date
- 2008
- Source
- Cell Metabolism 8(6): 502-511 (Journal)
- Registered Authors
- Keywords
- HUMDISEASE
- MeSH Terms
-
- Hepcidins
- HeLa Cells
- Humans
- Endoplasmic Reticulum/metabolism
- Membrane Proteins/biosynthesis
- Membrane Proteins/metabolism*
- Amino Acid Substitution
- Cell Membrane/metabolism
- Cells, Cultured
- Protein Processing, Post-Translational
- Signal Transduction
- Animals
- Zebrafish
- Antimicrobial Cationic Peptides/antagonists & inhibitors*
- Antimicrobial Cationic Peptides/biosynthesis
- Antimicrobial Cationic Peptides/metabolism
- Promoter Regions, Genetic
- GPI-Linked Proteins
- Serine Endopeptidases/biosynthesis
- Serine Endopeptidases/metabolism*
- PubMed
- 18976966 Full text @ Cell Metab.
Citation
Silvestri, L., Pagani, A., Nai, A., De Domenico, I., Kaplan, J., and Camaschella, C. (2008) The Serine Protease Matriptase-2 (TMPRSS6) Inhibits Hepcidin Activation by Cleaving Membrane Hemojuvelin. Cell Metabolism. 8(6):502-511.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping