The Serine Protease Matriptase-2 (TMPRSS6) Inhibits Hepcidin Activation by Cleaving Membrane Hemojuvelin

被引：465

作者：

Silvestri, Laura ^{[1
]}

Pagani, Alessia ^{[1
]}

Nai, Antonella ^{[1
]}

De Domenico, Ivana ^{[2
,3
]}

Kaplan, Jerry ^{[3
]}

Camaschella, Clara ^{[1
]}

机构：

[1] Univ Vita Salute San Raffaele, IRCCS San Raffaele, Milan, Italy

[2] Univ Utah, Dept Med, Sch Med, Salt Lake City, UT 84112 USA

[3] Univ Utah, Dept Pathol, Sch Med, Salt Lake City, UT 84112 USA

来源：

CELL METABOLISM | 2008年 / 8卷 / 06期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1016/j.cmet.2008.09.012

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The liver peptide hepcidin regulates body iron, is up-regulated 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.

引用

页码：502 / 511

页数：10

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