Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 320 (5879): 1088-1092

Copyright © 2008 by the American Association for the Advancement of Science

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 Beutler1*

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.

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. E-mail: bruce{at}

Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to proliferative Ras/RAF and nutrient-dependent mTOR signaling.
K. Mleczko-Sanecka, F. Roche, A. Rita da Silva, D. Call, F. D'Alessio, A. Ragab, P. E. Lapinski, R. Ummanni, U. Korf, C. Oakes, et al. (2014)
Blood 123, 1574-1585
   Abstract »    Full Text »    PDF »
How I treat unexplained refractory iron deficiency anemia.
C. Hershko and C. Camaschella (2014)
Blood 123, 326-333
   Abstract »    Full Text »    PDF »
The liver: conductor of systemic iron balance.
D. Meynard, J. L. Babitt, and H. Y. Lin (2014)
Blood 123, 168-176
   Abstract »    Full Text »    PDF »
Iron and hepcidin: a story of recycling and balance.
C. Camaschella (2013)
Hematology 2013, 1-8
   Abstract »    Full Text »    PDF »
Systemic Iron Homeostasis.
T. Ganz (2013)
Physiol Rev 93, 1721-1741
   Abstract »    Full Text »    PDF »
Associations of common variants in HFE and TMPRSS6 with iron parameters are independent of serum hepcidin in a general population: a replication study.
T. E. Galesloot, A. J. Geurts-Moespot, M. den Heijer, F. C. G. J. Sweep, R. E. Fleming, L. A. L. M. Kiemeney, S. H. Vermeulen, and D. W. Swinkels (2013)
J. Med. Genet. 50, 593-598
   Abstract »    Full Text »    PDF »
Human L-ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome.
A. Cozzi, P. Santambrogio, D. Privitera, V. Broccoli, L. I. Rotundo, B. Garavaglia, R. Benz, S. Altamura, J. S. Goede, M. U. Muckenthaler, et al. (2013)
J. Exp. Med. 210, 1779-1791
   Abstract »    Full Text »    PDF »
Profile of Bruce A. Beutler.
S. Ravindran (2013)
PNAS 110, 12857-12858
   Full Text »    PDF »
Screening Identifies the Chinese Medicinal Plant Caulis Spatholobi as an Effective HAMP Expression Inhibitor.
Y. Guan, P. An, Z. Zhang, F. Zhang, Y. Yu, Q. Wu, Y. Shi, X. Guo, Y. Tao, and F. Wang (2013)
J. Nutr. 143, 1061-1066
   Abstract »    Full Text »    PDF »
Iron Deficiency Anemia: A Common and Curable Disease.
J. L. Miller (2013)
Cold Spring Harb Perspect Med 3, a011866
   Abstract »    Full Text »    PDF »
Iron refractory iron deficiency anemia.
L. De Falco, M. Sanchez, L. Silvestri, C. Kannengiesser, M. U. Muckenthaler, A. Iolascon, L. Gouya, C. Camaschella, and C. Beaumont (2013)
Haematologica 98, 845-853
   Abstract »    Full Text »    PDF »
Identification and characterization of a novel murine allele of Tmprss6.
T. B. Bartnikas, A. U. Steinbicker, D. R. Campagna, S. Blevins, L. S. Woodward, C. Herrera, K. D. Bloch, M. J. Justice, and M. D. Fleming (2013)
Haematologica 98, 854-861
   Abstract »    Full Text »    PDF »
Inhibiting the hepcidin inhibitor for treatment of iron overload.
L. Silvestri (2013)
Blood 121, 1068-1069
   Full Text »    PDF »
An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe-/- mice and ameliorates anemia and iron overload in murine {beta}-thalassemia intermedia.
P. J. Schmidt, I. Toudjarska, A. K. Sendamarai, T. Racie, S. Milstein, B. R. Bettencourt, J. Hettinger, D. Bumcrot, and M. D. Fleming (2013)
Blood 121, 1200-1208
   Abstract »    Full Text »    PDF »
Hepcidin and the Iron-Infection Axis.
H. Drakesmith and A. M. Prentice (2012)
Science 338, 768-772
   Abstract »    Full Text »    PDF »
Late stage erythroid precursor production is impaired in mice with chronic inflammation.
O. D. Prince, J. M. Langdon, A. J. Layman, I. C. Prince, M. Sabogal, H. H. Mak, A. E. Berger, C. Cheadle, F. J. Chrest, Q. Yu, et al. (2012)
Haematologica 97, 1648-1656
   Abstract »    Full Text »    PDF »
Neogenin Interacts with Matriptase-2 to Facilitate Hemojuvelin Cleavage.
C. A. Enns, R. Ahmed, and A.-S. Zhang (2012)
J. Biol. Chem. 287, 35104-35117
   Abstract »    Full Text »    PDF »
Iron sensing and signalling.
R. Evstatiev and C. Gasche (2012)
Gut 61, 933-952
   Abstract »    Full Text »    PDF »
Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis.
M. Mastrogiannaki, P. Matak, J. R. R. Mathieu, S. Delga, P. Mayeux, S. Vaulont, and C. Peyssonnaux (2012)
Haematologica 97, 827-834
   Abstract »    Full Text »    PDF »
Deletion of TMPRSS6 attenuates the phenotype in a mouse model of {beta}-thalassemia.
A. Nai, A. Pagani, G. Mandelli, M. R. Lidonnici, L. Silvestri, G. Ferrari, and C. Camaschella (2012)
Blood 119, 5021-5029
   Abstract »    Full Text »    PDF »
TMPRSS6, but not TF, TFR2 or BMP2 variants are associated with increased risk of iron-deficiency anemia.
P. An, Q. Wu, H. Wang, Y. Guan, M. Mu, Y. Liao, D. Zhou, P. Song, C. Wang, L. Meng, et al. (2012)
Hum. Mol. Genet. 21, 2124-2131
   Abstract »    Full Text »    PDF »
Iron Metabolism: Interactions with Normal and Disordered Erythropoiesis.
T. Ganz and E. Nemeth (2012)
Cold Spring Harb Perspect Med 2, a011668
   Abstract »    Full Text »    PDF »
Association of TMPRSS6 polymorphisms with ferritin, hemoglobin, and type 2 diabetes risk in a Chinese Han population.
W. Gan, Y. Guan, Q. Wu, P. An, J. Zhu, L. Lu, L. Jing, Y. Yu, S. Ruan, D. Xie, et al. (2012)
Am J Clin Nutr 95, 626-632
   Abstract »    Full Text »    PDF »
Unraveling Mechanisms Regulating Systemic Iron Homeostasis.
K. E. Finberg (2011)
Hematology 2011, 532-537
   Abstract »    Full Text »    PDF »
Pathways for the regulation of hepcidin expression in anemia of chronic disease and iron deficiency anemia in vivo.
I. Theurl, A. Schroll, M. Nairz, M. Seifert, M. Theurl, T. Sonnweber, H. Kulaksiz, and G. Weiss (2011)
Haematologica 96, 1761-1769
   Abstract »    Full Text »    PDF »
{beta}-thalassemia: a model for elucidating the dynamic regulation of ineffective erythropoiesis and iron metabolism.
Y. Ginzburg and S. Rivella (2011)
Blood 118, 4321-4330
   Abstract »    Full Text »    PDF »
TMPRSS6 rs855791 modulates hepcidin transcription in vitro and serum hepcidin levels in normal individuals.
A. Nai, A. Pagani, L. Silvestri, N. Campostrini, M. Corbella, D. Girelli, M. Traglia, D. Toniolo, and C. Camaschella (2011)
Blood 118, 4459-4462
   Abstract »    Full Text »    PDF »
Association of HFE and TMPRSS6 genetic variants with iron and erythrocyte parameters is only in part dependent on serum hepcidin concentrations.
M. Traglia, D. Girelli, G. Biino, N. Campostrini, M. Corbella, C. Sala, C. Masciullo, F. Vigano, I. Buetti, G. Pistis, et al. (2011)
J. Med. Genet. 48, 629-634
   Abstract »    Full Text »    PDF »
Essential Role of Endocytosis of the Type II Transmembrane Serine Protease TMPRSS6 in Regulating Its Functionality.
F. Beliveau, C. Brule, A. Desilets, B. Zimmerman, S. A. Laporte, C. L. Lavoie, and R. Leduc (2011)
J. Biol. Chem. 286, 29035-29043
   Abstract »    Full Text »    PDF »
Low hepcidin accounts for the proinflammatory status associated with iron deficiency.
A. Pagani, A. Nai, G. Corna, L. Bosurgi, P. Rovere-Querini, C. Camaschella, and L. Silvestri (2011)
Blood 118, 736-746
   Abstract »    Full Text »    PDF »
Regulation of TMPRSS6 by BMP6 and iron in human cells and mice.
D. Meynard, V. Vaja, C. C. Sun, E. Corradini, S. Chen, C. Lopez-Otin, L. Grgurevic, C. C. Hong, M. Stirnberg, M. Gutschow, et al. (2011)
Blood 118, 747-756
   Abstract »    Full Text »    PDF »
Hepcidin and iron regulation, 10 years later.
T. Ganz (2011)
Blood 117, 4425-4433
   Abstract »    Full Text »    PDF »
Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice.
K. E. Finberg, R. L. Whittlesey, and N. C. Andrews (2011)
Blood 117, 4590-4599
   Abstract »    Full Text »    PDF »
Regulation of Type II Transmembrane Serine Proteinase TMPRSS6 by Hypoxia-inducible Factors: NEW LINK BETWEEN HYPOXIA SIGNALING AND IRON HOMEOSTASIS.
S. Lakhal, J. Schodel, A. R. M. Townsend, C. W. Pugh, P. J. Ratcliffe, and D. R. Mole (2011)
J. Biol. Chem. 286, 4090-4097
   Abstract »    Full Text »    PDF »
Suppression of hepatic hepcidin expression in response to acute iron deprivation is associated with an increase of matriptase-2 protein.
A.-S. Zhang, S. A. Anderson, J. Wang, F. Yang, K. DeMaster, R. Ahmed, C. P. Nizzi, R. S. Eisenstein, H. Tsukamoto, and C. A. Enns (2011)
Blood 117, 1687-1699
   Abstract »    Full Text »    PDF »
Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6.
A. Lenoir, J.-C. Deschemin, L. Kautz, A. J. Ramsay, M.-P. Roth, C. Lopez-Otin, S. Vaulont, and G. Nicolas (2011)
Blood 117, 647-650
   Abstract »    Full Text »    PDF »
Matriptase-2- and Proprotein Convertase-cleaved Forms of Hemojuvelin Have Different Roles in the Down-regulation of Hepcidin Expression.
J. E. Maxson, J. Chen, C. A. Enns, and A.-S. Zhang (2010)
J. Biol. Chem. 285, 39021-39028
   Abstract »    Full Text »    PDF »
Anemia of Inflammation.
C. N. Roy (2010)
Hematology 2010, 276-280
   Abstract »    Full Text »    PDF »
Immunoassay for human serum hemojuvelin.
C. Brasse-Lagnel, M. Poli, C. Lesueur, B. Grandchamp, A. Lavoinne, C. Beaumont, and S. Bekri (2010)
Haematologica 95, 2031-2037
   Abstract »    Full Text »    PDF »
Control of Systemic Iron Homeostasis by the Hemojuvelin-Hepcidin Axis.
A.-S. Zhang (2010)
Adv Nutr 1, 38-45
   Abstract »    Full Text »    PDF »
Transferrin receptor 2 and HFE regulate furin expression via mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) signaling. Implications for transferrin-dependent hepcidin regulation.
M. Poli, S. Luscieti, V. Gandini, F. Maccarinelli, D. Finazzi, L. Silvestri, A. Roetto, and P. Arosio (2010)
Haematologica 95, 1832-1840
   Abstract »    Full Text »    PDF »
Severe iron deficiency blunts the response of the iron regulatory gene Hamp and pro-inflammatory cytokines to lipopolysaccharide.
D. Darshan, D. M. Frazer, S. J. Wilkins, and G. J. Anderson (2010)
Haematologica 95, 1660-1667
   Abstract »    Full Text »    PDF »
Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice.
A. Nai, A. Pagani, L. Silvestri, and C. Camaschella (2010)
Blood 116, 851-852
   Full Text »    PDF »
Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis.
K. E. Finberg, R. L. Whittlesey, M. D. Fleming, and N. C. Andrews (2010)
Blood 115, 3817-3826
   Abstract »    Full Text »    PDF »
A genome-wide association analysis of serum iron concentrations.
T. Tanaka, C. N. Roy, W. Yao, A. Matteini, R. D. Semba, D. Arking, J. D. Walston, L. P. Fried, A. Singleton, J. Guralnik, et al. (2010)
Blood 115, 94-96
   Abstract »    Full Text »    PDF »
Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms.
A. J. Ramsay, V. Quesada, M. Sanchez, C. Garabaya, M. P. Sarda, M. Baiget, A. Remacha, G. Velasco, and C. Lopez-Otin (2009)
Hum. Mol. Genet. 18, 3673-3683
   Abstract »    Full Text »    PDF »
Type II Transmembrane Serine Proteases.
T. H. Bugge, T. M. Antalis, and Q. Wu (2009)
J. Biol. Chem. 284, 23177-23181
   Abstract »    Full Text »    PDF »
Hemojuvelin-Neogenin Interaction Is Required for Bone Morphogenic Protein-4-induced Hepcidin Expression.
A.-S. Zhang, F. Yang, J. Wang, H. Tsukamoto, and C. A. Enns (2009)
J. Biol. Chem. 284, 22580-22589
   Abstract »    Full Text »    PDF »
Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis.
A. J. Ramsay, J. D. Hooper, A. R. Folgueras, G. Velasco, and C. Lopez-Otin (2009)
Haematologica 94, 840-849
   Abstract »    Full Text »    PDF »
Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia.
L. Silvestri, F. Guillem, A. Pagani, A. Nai, C. Oudin, M. Silva, F. Toutain, C. Kannengiesser, C. Beaumont, C. Camaschella, et al. (2009)
Blood 113, 5605-5608
   Abstract »    Full Text »    PDF »
Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications.
I. Theurl, E. Aigner, M. Theurl, M. Nairz, M. Seifert, A. Schroll, T. Sonnweber, L. Eberwein, D. R. Witcher, A. T. Murphy, et al. (2009)
Blood 113, 5277-5286
   Abstract »    Full Text »    PDF »
Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo.
S. Soe-Lin, S. S. Apte, B. Andriopoulos Jr., M. C. Andrews, M. Schranzhofer, T. Kahawita, D. Garcia-Santos, and P. Ponka (2009)
PNAS 106, 5960-5965
   Abstract »    Full Text »    PDF »
Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis.
A. Iolascon, L. De Falco, and C. Beaumont (2009)
Haematologica 94, 395-408
   Abstract »    Full Text »    PDF »
Molecular mechanisms of normal iron homeostasis.
A.-S. Zhang and C. A. Enns (2009)
Hematology 2009, 207-214
   Abstract »    Full Text »    PDF »
An immunoassay for human serum hepcidin at last: Ganz klar?.
C. Brugnara (2008)
Blood 112, 3922-3923
   Full Text »    PDF »
Immunoassay for human serum hepcidin.
T. Ganz, G. Olbina, D. Girelli, E. Nemeth, and M. Westerman (2008)
Blood 112, 4292-4297
   Abstract »    Full Text »    PDF »
New insights into intestinal iron absorption.
W. H. Horl (2008)
Nephrol. Dial. Transplant. 23, 3063-3064
   Full Text »    PDF »
New and old players in the hepcidin pathway.
C. Camaschella and L. Silvestri (2008)
Haematologica 93, 1441-1444
   Full Text »    PDF »
A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron.
M. A. Melis, M. Cau, R. Congiu, G. Sole, S. Barella, A. Cao, M. Westerman, M. Cazzola, and R. Galanello (2008)
Haematologica 93, 1473-1479
   Abstract »    Full Text »    PDF »
Iron homeostasis: casting new roles.
K. E. Finberg (2008)
Blood 112, 2181
   Full Text »    PDF »
Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis.
A. R. Folgueras, F. M. de Lara, A. M. Pendas, C. Garabaya, F. Rodriguez, A. Astudillo, T. Bernal, R. Cabanillas, C. Lopez-Otin, and G. Velasco (2008)
Blood 112, 2539-2545
   Abstract »    Full Text »    PDF »
Two nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency.
F. Guillem, S. Lawson, C. Kannengiesser, M. Westerman, C. Beaumont, and B. Grandchamp (2008)
Blood 112, 2089-2091
   Abstract »    Full Text »    PDF »
The Regulation of Hepcidin and Its Effects on Systemic and Cellular Iron Metabolism.
M. D. Fleming (2008)
Hematology 2008, 151-158
   Abstract »    Full Text »    PDF »
Clinical Relevance of Anemia and Transfusion Iron Overload in Myelodysplastic Syndromes.
M. Cazzola, M. G. Della Porta, and L. Malcovati (2008)
Hematology 2008, 166-175
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882