The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin.
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.
Silvestri
Laura
L
Vita-Salute San Raffaele University, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, Milan, Italy.
Pagani
Alessia
A
Nai
Antonella
A
De Domenico
Ivana
I
Kaplan
Jerry
J
Camaschella
Clara
C
D019943:Amino Acid Substitution; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D058851:GPI-Linked Proteins; D006367:HeLa Cells; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D015027:Zebrafish
D023181:Antimicrobial Cationic Peptides; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C481006:HJV protein, human; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D008565:Membrane Proteins; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human