Cell metabolismPub Date : 2008-12-01Epub Date: 2008-10-30DOI: 10.1016/j.cmet.2008.09.012
Laura Silvestri, Alessia Pagani, Antonella Nai, Ivana De Domenico, Jerry Kaplan, Clara Camaschella
{"title":"The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin.","authors":"Laura Silvestri, Alessia Pagani, Antonella Nai, Ivana De Domenico, Jerry Kaplan, Clara Camaschella","doi":"10.1016/j.cmet.2008.09.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2008.09.012","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":"8 6","pages":"502-11"},"PeriodicalIF":0.0,"publicationDate":"2008-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2648389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}