The catalytic, stem, and transmembrane portions of matriptase-2 are required for suppressing the expression of the iron-regulatory hormone hepcidin (original) (raw)
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Low intracellular iron increases the stability of matriptase-2
The Journal of biological chemistry, 2014
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 d...
Biochemical Journal, 2007
Mammalian IRPs (iron regulatory proteins), IRP1 and IRP2, are cytosolic RNA-binding proteins that post-transcriptionally control the mRNA of proteins involved in storage, transport, and utilization of iron. In iron-replete cells, IRP2 undergoes degradation by the ubiquitin/proteasome pathway. Binding of haem to a 73aa-Domain (73-amino-acid domain) that is unique in IRP2 has been previously proposed as the initial iron-sensing mechanism. It is shown here that recombinant IRP2 and the 73aa-Domain are sensitive to proteolysis at the same site. NMR results suggest that the isolated 73aa-Domain is not structured. Iron-independent cleavage of IRP2 within the 73aa-Domain also occurs in lung cancer (H1299) cells. Haem interacts with a cysteine residue only in truncated forms of the 73aa-Domain, as shown by a series of complementary physicochemical approaches, including NMR, EPR and UV-visible absorption spectroscopy. In contrast, the cofactor is not ligated by the same residue in the full-length peptide or intact IRP2, although non-specific interaction occurs between these molecular forms and haem. Therefore it is unlikely that the iron-dependent degradation of IRP2 is mediated by haem binding to the intact 73aa-Domain, since the sequence resembling an HRM (haem-regulatory motif) in the 73aa-Domain does not provide an axial ligand of the cofactor unless this domain is cleaved.
Regulation of cellular iron metabolism
Iron is an essential but potentially hazardous biometal. Mammalian cells require sufficient amounts of iron to satisfy metabolic needs or to accomplish specialized functions. Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma mainly from intestinal enterocytes or reticuloendothelial macrophages. The binding of iron-laden transferrin to the cell-surface transferrin receptor 1 results in endocytosis and uptake of the metal cargo. Internalized iron is transported to mitochondria for the synthesis of haem or iron–sulfur clusters, which are integral parts of several metalloproteins, and excess iron is stored and detoxified in cytosolic ferritin. Iron metabolism is controlled at different levels and by diverse mechanisms. The present review summarizes basic concepts of iron transport, use and storage and focuses on the IRE (iron-responsive element)/IRP (iron-regulatory protein) system, a well known post-transcriptional regulatory circuit that not only maintains iron homoeostasis in various cell types, but also contributes to systemic iron balance.
An overview of molecular basis of iron metabolism regulation and the associated pathologies
Biochimica et biophysica acta, 2015
Iron is essential for several vital biological processes. Its deficiency or overload drive to the development of several pathologies. To maintain iron homeostasis, the organism controls the dietary iron absorption by enterocytes, its recycling by macrophages and storage in hepatocytes. These processes are mainly controlled by hepcidin, a liver-derived hormone which synthesis is regulated by iron levels, inflammation, infection, anemia and erythropoiesis. Besides the systemic regulation of iron metabolism mediated by hepcidin, cellular regulatory processes also occur. Cells are able to regulate themselves the expression of the iron metabolism-related genes through different post-transcriptional mechanisms, as the alternative splicing, microRNAs, the IRP/IREs system and the proteolytic cleavage. Whenever those mechanisms are disturbed, due to genetic or environmental factors, iron homeostasis is disrupted and iron related pathologies may arise.
Post-transcriptional regulation of cellular iron homeostasis
Cellular iron homeostasis is achieved by the coordinate and reciprocal post-transcriptional regulation of transferrin receptor 1 (TfR1) and ferritin expression, which are key molecules for iron acquisition and storage, respectively. The mechanism involves interactions between cytoplasmic iron regulatory proteins (IRP1 and IRP2) and iron responsive elements (IREs) located within non-coding sequences of TfR1 and ferritin mRNAs. In iron-deficient cells, IRE/IRP interactions stabilize TfR1 mRNA and inhibit the translation of the mRNAs encoding H-and L-ferritin. The RNA-binding activities of IRP1 and IRP2 are induced in iron deficiency. In iron-replete cells, IRP1 assembles a cubane [4Fe-4S] iron sulfur cluster (ISC), which Correspondence/Reprint request: Dr. K. Carine Fillebeen et al. # % prevents the binding to IREs and converts the protein to a (cytosolic) c-aconitase. By contrast, IRP2 undergoes ubiquitination and degradation by the proteasome. IRPs respond not only to cellular iron ...
Iron metabolism: current facts and future directions
Biochemia Medica, 2012
Iron metabolism has been intensively examined over the last decade and there are many new players in this field which are worth to be introduced. Since its discovery many studies confirmed role of liver hormone hepcidin as key regulator of iron metabolism and pointed out liver as the central organ of system iron homeostasis. Liver cells receive multiple signals related to iron balance and respond by transcriptional regulation of hepcidin expression. This liver hormone is negative regulator of iron metabolism that represses iron efflux from macrophages, hepatocytes and enterocytes by its binding to iron export protein ferroportin. Ferroportin degradation leads to cellular iron retention and decreased iron availability. At level of a cell IRE/IRP (iron responsive elements/iron responsive proteins) system allows tight regulation of iron assimilation that prevents an excess of free intracellular iron which could lead to oxidative stress and damage of DNA, proteins and lipid membranes by...
Blood, 2005
Cytosolic ferritin sequesters and stores iron and, consequently, protects cells against iron-mediated free radical damage. However, the function of the newly discovered mitochondrial ferritin (MtFt) is unknown. To examine the role of MtFt in cellular iron metabolism, we established a cell line that stably overexpresses mouse MtFt under the control of a tetracycline-responsive promoter. The overexpression of MtFt caused a dose-dependent iron deficiency in the cytosol that was revealed by increased RNA-binding activity of iron regulatory proteins (IRPs) along with an increase in transferrin receptor levels and decrease in cytosolic ferritin. Consequently, the induction of MtFt resulted in a dramatic increase in cellular iron uptake from transferrin, most of which was incorporated into MtFt. The induction of MtFt caused a shift of iron from cytosolic ferritin to MtFt. In addition, iron inserted into MtFt was less available for chelation than that in cytosolic ferritin and the expression of MtFt was associated with decreased mitochondrial and cytosolic aconitase activities, the latter being consistent with the increase in IRPbinding activity. In conclusion, our results indicate that overexpression of MtFt causes a dramatic change in intracellular iron homeostasis and that shunting iron to MtFt likely limits its availability for active iron proteins. (Blood. 2005;105: 2161-2167)