title: The serine protease TMPRSS6 is required to sense iron deficiency.
abstract: 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. 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.
authors.affiliation: Department of Genetics, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.forename: Ellen
authors.initials: E
authors.lastname: She
authors.forename: Terri
authors.initials: T
authors.lastname: Gelbart
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Truksa
authors.forename: Pauline
authors.initials: P
authors.lastname: Lee
authors.forename: Yu
authors.initials: Y
authors.lastname: Xia
authors.forename: Kevin
authors.initials: K
authors.lastname: Khovananth
authors.forename: Suzanne
authors.initials: S
authors.lastname: Mudd
authors.forename: Navjiwan
authors.initials: N
authors.lastname: Mann
authors.forename: Eva Marie Y
authors.initials: EM
authors.lastname: Moresco
authors.forename: Ernest
authors.initials: E
authors.lastname: Beutler
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
mesh_terms: D000748:Anemia, Macrocytic / Q000235:genetics / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism; D000090463:Iron Deficiencies; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D008565:Membrane Proteins; D007501:Iron; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human; C467801:matriptase 2