Regulation of type II transmembrane serine proteinase TMPRSS6 by hypoxia-inducible factors: New link between hypoxia signaling and iron homeostasis

Lakhal S, Schödel J, Townsend AR, Pugh CW, Ratcliffe PJ, Mole DR (2011)

Publication Type: Journal article

Publication year: 2011

Journal

Journal of Biological Chemistry American Society for Biochemistry and Molecular Biology

Book Volume: 286

Pages Range: 4090-4097

Journal Issue: 6

DOI: 10.1074/jbc.M110.173096

Abstract

Hepcidin is a liver-derived hormone with a key role in iron homeostasis. In addition to iron, it is regulated by inflammation and hypoxia, although mechanisms of hypoxic regulation remain unclear. In hepatocytes, hepcidin is induced by bone morphogenetic proteins (BMPs) through a receptor complex requiring hemojuvelin (HJV) as a co-receptor. Type II transmembrane serine proteinase (TMPRSS6) antagonizes hepcidin induction by BMPs by cleaving HJV from the cell membrane. Inactivating mutations in TMPRSS6 lead to elevated hepcidin levels and consequent iron deficiency anemia. Here we demonstrate that TMPRSS6 is up-regulated in hepatic cell lines by hypoxia and by other activators of hypoxia-inducible factor (HIF). We show that TMPRSS6 expression is regulated by both HIF-1α and HIF-2α. This HIF-dependent up-regulation of TMPRSS6 increases membrane HJV shedding and decreases hepcidin promoter responsiveness to BMP signaling in hepatocytes. Our results reveal a potential role for TMPRSS6 in hepcidin regulation by hypoxia and provide a new molecular link between oxygen sensing and iron homeostasis. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Authors with CRIS profile

Johannes Schödel

Involved external institutions

University of Oxford GB United Kingdom (GB) MRC Weatherall Institute Of Molecular Medicine GB United Kingdom (GB)

How to cite

APA:

Lakhal, S., Schödel, J., Townsend, A.R., Pugh, C.W., Ratcliffe, P.J., & Mole, D.R. (2011). Regulation of type II transmembrane serine proteinase TMPRSS6 by hypoxia-inducible factors: New link between hypoxia signaling and iron homeostasis. Journal of Biological Chemistry, 286(6), 4090-4097. https://doi.org/10.1074/jbc.M110.173096

MLA:

Lakhal, Samira, et al. "Regulation of type II transmembrane serine proteinase TMPRSS6 by hypoxia-inducible factors: New link between hypoxia signaling and iron homeostasis." Journal of Biological Chemistry 286.6 (2011): 4090-4097.

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