Submitted on February 28, 2008
Accepted on April 17, 2008
The Serine Protease TMPRSS6 Is Required to Sense Iron Deficiency
Xin Du 1, Ellen She 1, Terri Gelbart 2, Jaroslav Truksa 2, Pauline Lee 2, Yu Xia 1, Kevin Khovananth 1, Suzanne Mudd 1, Navjiwan Mann 1, Eva Marie Y. Moresco 1, Ernest Beutler 2, Bruce Beutler 1*
1 Department of Genetics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
* To whom correspondence should be addressed.
Bruce Beutler , E-mail: bruce{at}scripps.edu
Hepcidin, a liver-derived protein that restricts enteric iron absorption, is the key regulator of body iron content. Several proteins induce expression of the hepcidin-encoding gene Hamp in response to infection or high levels of iron. However, mechanism(s) of Hamp suppression during iron depletion are poorly understood. Here we describe mask, a recessive, chemically induced mutant mouse phenotype, characterized by progressive loss of body but not facial hair and microcytic anemia. The mask phenotype results from reduced absorption of dietary iron caused by high levels of hepcidin, and is due to a splicing defect in the transmembrane serine protease 6 gene Tmprss6. Overexpression of normal TMPRSS6 protein suppresses activation of the Hamp promoter, and the TMPRSS6 cytoplasmic domain mediates Hamp suppression via proximal promoter element(s). TMPRSS6 is an essential component of a pathway that detects iron deficiency and blocks Hamp transcription, permitting enhanced dietary iron absorption.
