![]() This type II transmembrane protease is composed of a short cytoplasmic domain, a transmembrane domain, and a large extracellular domain, which contains a membrane-proximal stem region, a predicted activation domain, and a C-terminal catalytic domain ( 18). TMPRSS6 is predominantly expressed in hepatocytes ( 17). Similar phenotypes are also reported in mouse models either with knockdown of both Tmprss6 alleles or with a truncated Tmprss6 that lacks the catalytic domain ( mask mice), indicating that iron-refractory iron-deficiency anemia is caused by lack-of-function mutations in TMPRSS6 ( 14, 15). Mutations in TMPRSS6 result in increased hepcidin expression, which leads to iron-refractory iron-deficiency anemia ( 13). Recent studies document the pivotal roles of hemojuvelin (HJV) 2 in the up-regulation of hepcidin expression ( 6, – 12) and matriptase-2 (MT2, encoded by the gene TMPRSS6 in humans and Tmprss6 in mice and rats) in the suppression of hepcidin expression. A high level of iron in the body up-regulates hepcidin expression thus providing a negative feedback to maintain iron homeostasis. In contrast, inappropriately high levels of hepcidin cause iron-deficiency anemia ( 1, 2, 5). Lack of hepcidin causes juvenile hemochromatosis, a particularly severe form of iron overload disorder ( 4). It is expressed on duodenal enterocytes, macrophages, and hepatocytes. Ferroportin is the only known iron exporter. It inhibits iron efflux into the circulation by binding to and targeting ferroportin on plasma membrane for degradation ( 3). Hepcidin is a 25-amino acid peptide secreted predominantly by hepatocytes. Hepcidin, a key iron regulatory hormone, plays an essential role in this process. Because humans cannot control the excretion of excess iron from the body, systemic iron homeostasis is maintained by coordinately regulating the iron absorption in the duodenum, iron recycling from senescent erythrocytes in macrophages, and mobilization of stored iron in the liver ( 1, 2). Iron is an essential nutrient for life, but it is also toxic when in excess. These results suggest that regulation of MT2 occurs at the level of protein degradation rather than by changes in the rate of internalization and translational or transcriptional mechanisms and that the cytoplasmic domain of MT2 is necessary for its regulation. Studies in mice showed that Tmprss6 mRNA was not regulated by iron nor the BMP-mediated signaling with no evident correlation with either Bmp6 mRNA or Id1 mRNA, a target of BMP signaling. Neither acute nor chronic iron deficiency was able to alter the association of Tmprss6 mRNA with polyribosomes in the liver of rats indicating a lack of translational regulation by low iron levels. We found that lack of the putative endocytosis motif in its cytoplasmic domain largely abolished the sensitivity of MT2 to iron depletion. Rather, studies using a membrane-permeable iron chelator, salicylaldehyde isonicotinoyl hydrazone, revealed that depletion of cellular iron was able to decrease the degradation of MT2 independently of internalization. This increase did not result from the inhibition of MT2 shedding from the cells. In HepG2 cells stably expressing the coding sequence of the MT2 gene, TMPRSS6, incubation with apo-transferrin or the membrane-impermeable iron chelator, deferoxamine mesylate salt, was able to increase MT2 levels. Here, we report that MT2 is up-regulated under iron deprivation. Hemojuvelin is a bone morphogenetic protein (BMP) co-receptor. It suppresses the expression of hepatic hepcidin, an iron regulatory hormone, by cleaving membrane hemojuvelin into an inactive form. Matriptase-2 (MT2) is a type II transmembrane serine protease that is predominantly expressed in hepatocytes. ![]()
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