The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin.

IF 30.9

Cell metabolism Pub Date : 2008-12-01 Epub Date: 2008-10-30 DOI:10.1016/j.cmet.2008.09.012

Laura Silvestri, Alessia Pagani, Antonella Nai, Ivana De Domenico, Jerry Kaplan, Clara Camaschella

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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.

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丝氨酸蛋白酶基质蛋白酶-2 （TMPRSS6）通过切割膜血凝素抑制hepcidin的激活。

肝肽hepcidin调节机体铁，在铁超载和炎症时上调，在铁缺乏/缺氧时下调。跨膜丝氨酸蛋白酶基质蛋白酶-2 （TMPRSS6）抑制hepcidin反应，其突变失活导致小鼠和人类缺铁性贫血。本研究证实了基质酶-2对hepcidin启动子的抑制作用；我们发现，在贫血的Mask小鼠（matpase -2(Mask)）中发现的缺乏丝氨酸蛋白酶结构域的matpase -2完全失活，而在遗传性缺铁患者中发现的突变体R774C抑制活性降低。matripase -2在质膜上切割hepcidin的调节因子-血少年素（HJV）；基质酶-2（MASK）没有裂解活性，人类突变体只有部分裂解能力。matripase -2通过外域与HJV相互作用，因为这种相互作用在matripase -2（MASK）中是保守的。斑马鱼中表达基质酶-2突变体导致贫血，证实了基质酶-2在铁代谢中的作用及其与HJV的相互作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Cell metabolism

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