Low intracellular iron increases the stability of matriptase-2 [Molecular Bases of Disease]

December 30th, 2014 by Zhao, N., Nizzi, C. P., Anderson, S. A., Wang, J., Ueno, A., Tsukamoto, H., Eisenstein, R. S., Enns, C. A., Zhang, A.-S.

Matriptase-2 (MT2) is a type II transmembrane serine protease that is predominantly expressed in hepatocytes. It suppresses the expression of hepatic hepcidin, an iron regulatory hormone, by cleaving membrane hemojuvelin (HJV) into an inactive form. HJV is a bone morphogenetic protein (BMP) co-receptor. Here we report that MT2 is upregulated under iron deprivation. In HepG2 cells stably expressing the coding sequence of MT2 gene, TMPRSS6, incubation with apo-transferrin or membrane impermeable iron chelator, desferroxamine, was able to increase MT2 levels. This increase did not result from the inhibition of MT2 shedding from the cells. Rather, studies using a membrane permeable iron chelator, SIH, revealed that depletion of cellular iron was able to decrease the degradation of MT2 independently of internalization. We found that lack of the putative endocytosis motif in its cytoplasmic domain largely abolished the sensitivity of MT2 to iron-depletion. 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. Studies in mice showed that Tmprss6 mRNA was not regulated by iron or the BMP-mediated signaling with no evident correlation with either Bmp6 mRNA or Id1 mRNA, a target of BMP signaling. 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.