Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis.

Abstract:

: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.

journal_name

Blood

journal_title

Blood

authors

Folgueras AR,de Lara FM,Pendás AM,Garabaya C,Rodríguez F,Astudillo A,Bernal T,Cabanillas R,López-Otín C,Velasco G

doi

10.1182/blood-2008-04-149773

subject

Has Abstract

pub_date

2008-09-15 00:00:00

pages

2539-45

issue

6

eissn

0006-4971

issn

1528-0020

pii

blood-2008-04-149773

journal_volume

112

pub_type

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