Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis.
Proteolytic events at the cell surface are essential in the regulation of signal transduction pathways. During the past years, the family of type II transmembrane serine proteases (TTSPs) has acquired an increasing relevance because of their privileged localization at the cell surface, although our current understanding of the biologic function of most TTSPs is limited. Here we show that matriptase-2 (Tmprss6), a recently described member of the TTSP family, is an essential regulator of iron homeostasis. Thus, Tmprss6(-/-) mice display an overt phenotype of alopecia and a severe iron deficiency anemia. These hematologic alterations found in Tmprss6(-/-) mice are accompanied by a marked up-regulation of hepcidin, a negative regulator of iron export into plasma. Likewise, Tmprss6(-/-) mice have reduced ferroportin expression in the basolateral membrane of enterocytes and accumulate iron in these cells. Iron-dextran therapy rescues both alopecia and hematologic alterations of Tmprss6(-/-) mice, providing causal evidence that the anemic phenotype of these mutant mice results from the blockade of intestinal iron export into plasma after dietary absorption. On the basis of these findings, we conclude that matriptase-2 activity represents a novel and relevant step in hepcidin regulation and iron homeostasis.
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Spain.
Alicia R
AR
Folgueras
Fernando Martín
FM
de Lara
Alberto M
AM
Pendás
Cecilia
C
Garabaya
Francisco
F
Rodríguez
Aurora
A
Astudillo
Teresa
T
Bernal
Rubén
R
Cabanillas
Carlos
C
López-Otín
Gloria
G
Velasco
D000505:Alopecia / Q000209:etiology; D018798:Anemia, Iron-Deficiency / Q000209:etiology; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D064451:Hepcidins; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D012697:Serine Endopeptidases / Q000502:physiology*
D023181:Antimicrobial Cationic Peptides; C579599:Hamp protein, mouse; D064451:Hepcidins; D008565:Membrane Proteins; D007501:Iron; D012697:Serine Endopeptidases; C467801:matriptase 2