Medline ® Abstract for Reference 67
of 'Regulation of iron balance'
The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin.
Silvestri L, Pagani A, Nai A, De Domenico I, Kaplan J, Camaschella C
Cell Metab. 2008;8(6):502. Epub 2008 Oct 30.
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.
Vita-Salute San Raffaele University, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, Milan, Italy.