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Mark D. Fleming - One of the best experts on this subject based on the ideXlab platform.
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RNAi-mediated reduction of hepatic TMPRSS6 diminishes anemia and secondary iron overload in a splenectomized mouse model of β-thalassemia intermedia.
American journal of hematology, 2018Co-Authors: Paul J. Schmidt, Kaifeng Liu, Gary A. Visner, Kevin Fitzgerald, Shannon Fishman, Tim Racie, Julia Hettinger, James Butler, Mark D. FlemingAbstract:Diminished β-globin synthesis in β-thalassemia is associated with ineffective erythropoiesis, leading to secondary iron overload caused by inappropriately low levels of hepcidin and to splenomegaly in the symptomatic thalassemias. Splenectomy is often employed in patients with β-thalassemia to reduce hemolysis. Expression of the iron regulatory peptide hormone hepcidin is repressed by the serine protease TMPRSS6. Hepcidin induction by RNAi-mediated inhibition of TMPRSS6 expression reduces iron overload and mitigates anemia in murine models of β-thalassemia intermedia. To interrogate the efficacy of RNAi-mediated reduction of TMPRSS6 in splenectomized β-thalassemia, splenectomized β-thalassemic Hbbth3/+ animals were treated with a GalNAc-conjugated siRNA targeting TMPRSS6 (GalNAc-TMPRSS6) and their hematological and iron parameters monitored. We demonstrate that treatment with GalNAc-TMPRSS6 significantly diminishes TMPRSS6 expression and appropriately elevates hepcidin expression in splenectomized Hbbth3/+ animals. Similar to unsplenectomized animals, treated animals have markedly improved anemia due to diminished ineffective erythropoiesis and reduced iron loading in both serum and tissue. These results suggest that RNAi-mediated reduction of TMPRSS6 may have positive outcomes even in splenectomized β-thalassemia patients.
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combination therapy with a TMPRSS6 rnai therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β thalassemia intermedia
American Journal of Hematology, 2015Co-Authors: Paul J. Schmidt, Kevin Fitzgerald, Tim Racie, James Butler, Mark Westerman, Mark D. FlemingAbstract:β-thalassemias result from diminished β-globin synthesis and are associated with ineffective erythropoiesis and secondary iron overload caused by inappropriately low levels of the iron regulatory hormone hepcidin. The serine protease TMPRSS6 attenuates hepcidin production in response to iron stores. Hepcidin induction reduces iron overload and mitigates anemia in murine models of β-thalassemia intermedia. To further interrogate the efficacy of an RNAi-therapeutic downregulating TMPRSS6, β-thalassemic Hbbth3/+ animals on an iron replete, an iron deficient, or an iron replete diet also containing the iron chelator deferiprone were treated with TMPRSS6 siRNA. We demonstrate that the total body iron burden is markedly improved in Hbbth3/+ animals treated with siRNA and chelated with oral deferiprone, representing a significant improvement compared to either compound alone. These data indicate that siRNA suppression of TMPRSS6, in conjunction with oral iron chelation therapy, may prove superior for treatment of anemia and secondary iron loading seen in β-thalassemia intermedia. Am. J. Hematol. 90:310–313, 2015. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.
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combination therapy with a TMPRSS6 rnai therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β thalassemia intermedia short title TMPRSS6 sirna and deferiprone combination therapy in mur
2014Co-Authors: Paul J. Schmidt, Kevin Fitzgerald, Tim Racie, James Butler, Mark Westerman, Mark D. FlemingAbstract:β-thalassemias result from diminished β-globin synthesis and are associated with ineffective erythropoiesis and secondary iron overload caused by inappropriately low levels of the iron regulatory hormone hepcidin. The serine protease TMPRSS6 attenuates hepcidin production in response to iron stores. Hepcidin induction reduces iron overload and mitigates anemia in murine models of β-thalassemia intermedia. To further interrogate the efficacy of an RNAitherapeutic downregulating TMPRSS6, β-thalassemic Hbb animals on an iron replete, an iron deficient, or an iron replete diet also containing the iron chelator deferiprone were treated with TMPRSS6 siRNA. We demonstrate that the total body iron burden is markedly improved in Hbb animals treated with siRNA and chelated with oral deferiprone, representing a significant improvement compared to either compound alone. These data indicate that siRNA suppression of TMPRSS6, in conjunction with oral iron chelation therapy, may prove superior for treatment of anemia and secondary iron loading seen in β-thalassemia intermedia. Page 2 of 13 John Wiley & Sons American Journal of Hematology This article is protected by copyright. All rights reserved.
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An RNAi-Therapeutic Targeting TMPRSS6, in Conjunction With Oral Chelator Therapy, Ameliorates Anemia and Additively Diminishes Secondary Iron Overload In a Mouse Model Of β-Thalassemia Intermedia
Blood, 2013Co-Authors: Paul J. Schmidt, Kevin Fitzgerald, Tim Racie, James Butler, Mark D. FlemingAbstract:β-Thalassemias are a group of inherited blood disorders caused by loss of β-globin synthesis and are characterized by anemia, extramedullary hematopoiesis and ineffective erythropoiesis leading to secondary iron overload. Increased iron absorption is due to inappropriately low levels of the liver hormone, hepcidin ( HAMP ). The membrane serine protease Matriptase-2 ( TMPRSS6 ) attenuates BMP-mediated HAMP induction by cleaving the BMP co-receptor, hemojuvelin ( HJV ). Previously, we demonstrated that an RNAi-therapeutic targeting TMPRSS6 elevates hepcidin expression and reduces disease severity in the Hbb th3/+ mouse model of β-Thalassemia intermedia ( Blood. 2013; 14;121(7):1200-8). To further interrogate the efficacy of this therapeutic approach, Hbb th3/+ animals were treated with a siRNA directed against TMPRSS6 on a replete 50ppm iron diet, a low iron diet (3-5ppm iron) or a 50ppm iron diet containing deferiprone. Systemic administration of an siRNA directed against TMPRSS6 in the three diet conditions leads to significant inhibition of TMPRSS6 mRNA in the livers of Hbb th3/+ mice with concomitant elevation in hepcidin expression. In correspondence with earlier studies, we demonstrate here that TMPRSS6 silencing in animals under each of the three diet regimens leads to a significant improvement in the anemia of Hbb th3/+ mice as evidenced by increased total hemoglobin. Furthermore, hallmarks of ineffective erythropoiesis, including splenomegaly and reticulocytosis, were decreased in all TMPRSS6 silenced Hbb th3/+ animals. If untreated, excessive iron loading in humans with β-Thalassemia leads to tissue iron deposition and eventual organ damage and failure. Importantly, here we demonstrate that the total body iron burden of Hbb th3/+ mice, as assessed by non-heme liver iron, is decreased by almost 30% in animals chelated with oral deferiprone and treated with TMPRSS6 siRNA. A similar diminution of iron deposition is not evident in animals on a low iron diet or in mice fed deferiprone alone. Taken together, this data suggest that siRNA suppression of TMPRSS6 , in conjunction with chelation therapy, may provide an improved modality for treatment of the anemia and secondary iron loading seen in hemoglobinopathies such as β-Thalassemia. Disclosures: Racie: Alnylam Pharmaceutical, Inc: Employment. Butler: Alnylam Pharmaceutical, Inc: Employment. Fitzgerald: Alnylam: Employment. Fleming: Alnylam Pharmaceutical, Inc: Research Funding.
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an rnai therapeutic targeting TMPRSS6 decreases iron overload in hfe mice and ameliorates anemia and iron overload in murine β thalassemia intermedia
Blood, 2013Co-Authors: Paul J. Schmidt, Tim Racie, Julia Hettinger, Anoop K. Sendamarai, Ivanka Toudjarska, David Bumcrot, Stuart Milstein, Brian Bettencourt, Mark D. FlemingAbstract:Mutations in HFE lead to hereditary hemochromatosis (HH) because of inappropriately high iron uptake from the diet resulting from decreased hepatic expression of the iron-regulatory hormone hepcidin. β-thalassemia is a congenital anemia caused by partial or complete loss of β-globin synthesis causing ineffective erythropoiesis, anemia, decreased hepcidin production, and secondary iron overload. TMPRSS6 is postulated to regulate hepcidin production by cleaving Hemojuvelin (Hjv), a key modulator of hepcidin expression, from the hepatocyte surface. On this basis, we hypothesized that treatment of mouse models of HH (Hfe−/−) and β-thalassemia intermedia (Hbbth3/+) with TMPRSS6 siRNA formulated in lipid nanoparticles (LNPs) that are preferentially taken up by the liver would increase hepcidin expression and lessen the iron loading in both models. In the present study, we demonstrate that LNP-TMPRSS6 siRNA treatment of Hfe−/− and Hbbth3/+ mice induces hepcidin and diminishes tissue and serum iron levels. Furthermore, LNP-TMPRSS6 siRNA treatment of Hbbth3/+ mice substantially improved the anemia by altering RBC survival and ineffective erythropoiesis. Our results indicate that pharmacologic manipulation of TMPRSS6 with RNAi therapeutics isa practical approach to treating iron overload diseases associated with diminished hepcidin expression and may have efficacy in modifying disease-associated morbidities of β-thalassemia intermedia.
Richard Leduc - One of the best experts on this subject based on the ideXlab platform.
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Functional diversity of TMPRSS6 isoforms and variants expressed in hepatocellular carcinoma cell lines
Scientific reports, 2018Co-Authors: Sébastien P. Dion, François Béliveau, Antoine Désilets, Louis-philippe Morency, Rafael Najmanovich, Richard LeducAbstract:TMPRSS6, also known as matriptase-2, is a type II transmembrane serine protease that plays a major role in iron homeostasis by acting as a negative regulator of hepcidin production through cleavage of the BMP co-receptor haemojuvelin. Iron-refractory iron deficiency anaemia (IRIDA), an iron metabolism disorder, is associated with mutations in the TMPRSS6 gene. By analysing RNA-seq data encoding TMPRSS6 isoforms and other proteins involved in hepcidin production, we uncovered significant differences in expression levels between hepatocellular carcinoma (HCC) cell lines and normal human liver samples. Most notably, TMPRSS6 and HAMP expression was found to be much lower in HepG2 and Huh7 cells when compared to human liver samples. Furthermore, we characterized the common TMPRSS6 polymorphism V736A identified in Hep3B cells, the V795I mutation found in HepG2 cells, also associated with IRIDA, and the G603R substitution recently detected in two IRIDA patients. While variant V736A is as active as wild-type TMPRSS6, mutants V795I and G603R displayed significantly reduced proteolytic activity. Our results provide important information about commonly used liver cell models and shed light on the impact of two TMPRSS6 mutations associated with IRIDA.
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Transcriptome analysis reveals TMPRSS6 isoforms with distinct functionalities.
Journal of cellular and molecular medicine, 2018Co-Authors: Sébastien P. Dion, François Béliveau, Antoine Désilets, Mariana Gabriela Ghinet, Richard LeducAbstract:TMPRSS6 (matriptase-2) is a type II transmembrane serine protease involved in iron homoeostasis. At the cell surface of hepatocytes, TMPRSS6 cleaves haemojuvelin (HJV) and regulates the BMP/SMAD signalling pathway leading to production of hepcidin, a key regulator of iron absorption. Although four TMPRSS6 human isoforms and three mice TMPRSS6 isoforms are annotated in databases (Ensembl and RefSeq), their relative expression or activity has not been studied. Analyses of RNA-seq data and RT-PCR from human tissues reveal that TMPRSS6 isoform 1 (TMPRSS6-1) and 3 are mostly expressed in human testis while TMPRSS6-2 and TMPRSS6-4 are the main transcripts expressed in human liver, testis and pituitary. Furthermore, we confirm the existence and analyse the relative expression of three annotated mice TMPRSS6 isoforms. Using heterologous expression in HEK293 and Hep3B cells, we show that all human TMPRSS6 isoforms reach the cell surface but only TMPRSS6-1 undergoes internalization. Moreover, truncated TMPRSS6-3 or catalytically altered TMPRSS6-4 interact with HJV and prevent its cleavage by TMPRSS6-2, suggesting their potential role as dominant negative isoforms. Taken together, our results highlight the importance of understanding the precise function of each TMPRSS6 isoforms both in human and in mouse.
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Essential Role of Endocytosis of the Type II Transmembrane Serine Protease TMPRSS6 in Regulating Its Functionality
The Journal of biological chemistry, 2011Co-Authors: François Béliveau, Antoine Désilets, Cédric Brulé, Brandon Zimmerman, Stéphane A. Laporte, Christine Lavoie, Richard LeducAbstract:Abstract The type II transmembrane serine protease TMPRSS6 (also known as matriptase-2) controls iron homeostasis through its negative regulation of expression of hepcidin, a key hormone involved in iron metabolism. Upstream of the hepcidin-regulated signaling pathway, TMPRSS6 cleaves its target substrate hemojuvelin (HJV) at the plasma membrane, but the dynamics of the cell-surface expression of the protease have not been addressed. Here, we report that TMPRSS6 undergoes constitutive internalization in transfected HEK293 cells and in two human hepatic cell lines, HepG2 and primary hepatocytes, both of which express TMPRSS6 endogenously. Cell surface-labeled TMPRSS6 was internalized and was detected in clathrin- and AP-2-positive vesicles via a dynamin-dependent pathway. The endocytosed TMPRSS6 next transited in early endosomes and then to lysosomes. Internalization of TMPRSS6 is dependent on specific residues within its N-terminal cytoplasmic domain, as site-directed mutagenesis of these residues abrogated internalization and maintained the enzyme at the cell surface. Cells coexpressing these mutants and HJV produced significantly decreased levels of hepcidin compared with wild-type TMPRSS6 due to the sustained cleavage of HJV at the cell surface by TMPRSS6 mutants. Our results underscore for the first time the importance of TMPRSS6 trafficking at the plasma membrane in the regulation of hepcidin expression, an event that is essential for iron homeostasis.
Jan Krijt - One of the best experts on this subject based on the ideXlab platform.
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Erythropoietin administration increases splenic erythroferrone protein content and liver TMPRSS6 protein content in rats.
Blood cells molecules & diseases, 2017Co-Authors: Iuliia Gurieva, Jaroslav Truksa, Jana Frýdlová, Martin Vokurka, Zuzana Rychtarcikova, Jan KrijtAbstract:Erythroferrone (ERFE) and TMPRSS6 are important proteins in the regulation of iron metabolism. The objective of the study was to examine splenic ERFE and liver TMPRSS6 synthesis in rats treated with a combination of iron and erythropoietin (EPO). EPO was administered to female Wistar rats at 600U/day for four days, iron-pretreated rats received 150mg of iron before EPO treatment. Content of ERFE and TMPRSS6 proteins was determined by commercial antibodies. Iron pretreatment prevented the EPO-induced decrease in hepcidin expression. Content of phosphorylated SMAD 1,5,8 proteins was decreased in the liver by both EPO and iron plus EPO treatment. Fam132b expression in the spleen was increased both by EPO and iron plus EPO treatments; these treatments also significantly induced splenic Fam132a expression. ERFE protein content in the spleen was increased both by EPO and iron plus EPO to a similar extent. EPO administration increased TMPRSS6 content in the plasma membrane-enriched fraction of liver homogenate; in iron-pretreated rats, this increase was abolished. The results confirm that iron pretreatment prevents the EPO-induced decrease in liver Hamp expression. This effect probably occurs despite high circulating ERFE levels, since EPO-induced ERFE protein synthesis is not influenced by iron pretreatment.
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Effect of Erythropoietin, Iron Deficiency and Iron Overload on Liver Matriptase-2 (TMPRSS6) Protein Content in Mice and Rats
PLOS ONE, 2016Co-Authors: Jana Frýdlová, Jaroslav Truksa, Martin Vokurka, Iuliia Gurieva, Petr Přikryl, Lucas L. Falke, Jan KrijtAbstract:Matriptase-2 (TMPRSS6) is an important negative regulator of hepcidin expression; however, the effects of iron overload or accelerated erythropoiesis on liver TMPRSS6 protein content in vivo are largely unknown. We determined TMPRSS6 protein content in plasma membrane-enriched fractions of liver homogenates by immunoblotting, using a commercial antibody raised against the catalytic domain of TMPRSS6. Plasma membrane-enriched fractions were obtained by centrifugation at 3000 g and washing. TMPRSS6 was detected in the 3000 g fraction as a 120 kDa full-length protein in both mice and rats. Feeding of iron-deficient diet as well as erythropoietin treatment increased TMPRSS6 protein content in rats and mice by a posttranscriptional mechanism; the increase in TMPRSS6 protein by erythropoietin was also observed in Bmp6-mutant mice. Administration of high doses of iron to mice (200, 350 and 700 mg/kg) decreased TMPRSS6 protein content. Hemojuvelin was detected in the plasma membrane-enriched fractions of control animals as a full length protein of approximately 52 kDa; in iron deficient animals, the full length protein was partially cleaved at the N-terminus, resulting in an additional weak band of approximately 47 kDa. In livers from hemojuvelin-mutant mice, TMPRSS6 protein content was strongly decreased, suggesting that intact hemojuvelin is necessary for stable TMPRSS6 expression in the membrane. Overall, the results demonstrate posttranscriptional regulation of liver TMPRSS6 protein by iron status and erythropoietin administration, and provide support for the interaction of TMPRSS6 and hemojuvelin proteins in vivo.
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Liver hemojuvelin protein levels in mice deficient in matriptase-2 (TMPRSS6).
Blood Cells Molecules and Diseases, 2011Co-Authors: Jan Krijt, Yuzo Fujikura, Andrew J. Ramsay, Gloria Velasco, Emanuel NecasAbstract:Abstract Mutations of the TMPRSS6 gene, encoding the serine protease matriptase-2, lead to iron-refractory iron deficiency anemia. Matriptase-2 is a potent negative regulator of hepcidin. Based on in vitro data, it has recently been proposed that matriptase-2 decreases hepcidin synthesis by cleaving membrane hemojuvelin, a key protein of the hepcidin-regulatory pathway. However, in vivo evidence for this mechanism of action of matriptase-2 is lacking. To investigate the hemojuvelin–matriptase-2 interaction in vivo, an immunoblot assay for liver membrane hemojuvelin was optimized using hemojuvelin-mutant mice as a negative control. In wild-type mice, two hemojuvelin-specific bands of 35 kDa and 20 kDa were detected in mouse liver membrane fraction under reducing conditions; under non-reducing conditions, a single band of approximately 50 kDa was seen. Phosphatidylinositol-specific phospholipase C treatment confirmed binding of the detected protein to the cell membrane by a glycosylphosphatidylinositol anchor, indicating that the major form of mouse liver membrane hemojuvelin is a glycosylphosphatidylinositol-bound heterodimer. Unexpectedly, comparison of liver homogenates from TMPRSS6+/+ and TMPRSS6−/− mice revealed significantly decreased, rather than increased, hemojuvelin heterodimer content in TMPRSS6−/− mice. These data do not provide direct support for the concept that matriptase-2 cleaves membrane hemojuvelin and may indicate that, in vivo, the role of matriptase-2 in the regulation of hepcidin gene expression is more complex.
François Béliveau - One of the best experts on this subject based on the ideXlab platform.
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Discovery and Development of TMPRSS6 Inhibitors Modulating Hepcidin Levels in Human Hepatocytes.
Cell chemical biology, 2019Co-Authors: François Béliveau, Sébastien P. Dion, Antoine Désilets, Mariana Gabriela Ghinet, Aarti Tarkar, Pierre-luc Boudreault, Catherine St-georges, Eric Marsault, Daniel Paone, Jon L. CollinsAbstract:Iron overload disorders are characterized by the body's inability to regulate iron absorption and its storage which can lead to organ failures. Accumulated evidence has revealed that hepcidin, the master regulator of iron homeostasis, is negatively modulated by TMPRSS6 (matriptase-2), a liver-specific type II transmembrane serine protease (TTSP). Here, we report that treatment with a peptidomimetic inhibitor affecting TMPRSS6 activity increases hepcidin production in hepatic cells. Moreover, similar effects were observed when using non-peptidic inhibitors obtained through optimization of hits from high-throughput screening. Using HepG2 cells and human primary hepatocytes, we show that TMPRSS6 inhibitors block TMPRSS6-dependent hemojuvelin cleavage and increase HAMP expression and levels of secreted hepcidin.
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Functional diversity of TMPRSS6 isoforms and variants expressed in hepatocellular carcinoma cell lines
Scientific reports, 2018Co-Authors: Sébastien P. Dion, François Béliveau, Antoine Désilets, Louis-philippe Morency, Rafael Najmanovich, Richard LeducAbstract:TMPRSS6, also known as matriptase-2, is a type II transmembrane serine protease that plays a major role in iron homeostasis by acting as a negative regulator of hepcidin production through cleavage of the BMP co-receptor haemojuvelin. Iron-refractory iron deficiency anaemia (IRIDA), an iron metabolism disorder, is associated with mutations in the TMPRSS6 gene. By analysing RNA-seq data encoding TMPRSS6 isoforms and other proteins involved in hepcidin production, we uncovered significant differences in expression levels between hepatocellular carcinoma (HCC) cell lines and normal human liver samples. Most notably, TMPRSS6 and HAMP expression was found to be much lower in HepG2 and Huh7 cells when compared to human liver samples. Furthermore, we characterized the common TMPRSS6 polymorphism V736A identified in Hep3B cells, the V795I mutation found in HepG2 cells, also associated with IRIDA, and the G603R substitution recently detected in two IRIDA patients. While variant V736A is as active as wild-type TMPRSS6, mutants V795I and G603R displayed significantly reduced proteolytic activity. Our results provide important information about commonly used liver cell models and shed light on the impact of two TMPRSS6 mutations associated with IRIDA.
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Transcriptome analysis reveals TMPRSS6 isoforms with distinct functionalities.
Journal of cellular and molecular medicine, 2018Co-Authors: Sébastien P. Dion, François Béliveau, Antoine Désilets, Mariana Gabriela Ghinet, Richard LeducAbstract:TMPRSS6 (matriptase-2) is a type II transmembrane serine protease involved in iron homoeostasis. At the cell surface of hepatocytes, TMPRSS6 cleaves haemojuvelin (HJV) and regulates the BMP/SMAD signalling pathway leading to production of hepcidin, a key regulator of iron absorption. Although four TMPRSS6 human isoforms and three mice TMPRSS6 isoforms are annotated in databases (Ensembl and RefSeq), their relative expression or activity has not been studied. Analyses of RNA-seq data and RT-PCR from human tissues reveal that TMPRSS6 isoform 1 (TMPRSS6-1) and 3 are mostly expressed in human testis while TMPRSS6-2 and TMPRSS6-4 are the main transcripts expressed in human liver, testis and pituitary. Furthermore, we confirm the existence and analyse the relative expression of three annotated mice TMPRSS6 isoforms. Using heterologous expression in HEK293 and Hep3B cells, we show that all human TMPRSS6 isoforms reach the cell surface but only TMPRSS6-1 undergoes internalization. Moreover, truncated TMPRSS6-3 or catalytically altered TMPRSS6-4 interact with HJV and prevent its cleavage by TMPRSS6-2, suggesting their potential role as dominant negative isoforms. Taken together, our results highlight the importance of understanding the precise function of each TMPRSS6 isoforms both in human and in mouse.
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Essential Role of Endocytosis of the Type II Transmembrane Serine Protease TMPRSS6 in Regulating Its Functionality
The Journal of biological chemistry, 2011Co-Authors: François Béliveau, Antoine Désilets, Cédric Brulé, Brandon Zimmerman, Stéphane A. Laporte, Christine Lavoie, Richard LeducAbstract:Abstract The type II transmembrane serine protease TMPRSS6 (also known as matriptase-2) controls iron homeostasis through its negative regulation of expression of hepcidin, a key hormone involved in iron metabolism. Upstream of the hepcidin-regulated signaling pathway, TMPRSS6 cleaves its target substrate hemojuvelin (HJV) at the plasma membrane, but the dynamics of the cell-surface expression of the protease have not been addressed. Here, we report that TMPRSS6 undergoes constitutive internalization in transfected HEK293 cells and in two human hepatic cell lines, HepG2 and primary hepatocytes, both of which express TMPRSS6 endogenously. Cell surface-labeled TMPRSS6 was internalized and was detected in clathrin- and AP-2-positive vesicles via a dynamin-dependent pathway. The endocytosed TMPRSS6 next transited in early endosomes and then to lysosomes. Internalization of TMPRSS6 is dependent on specific residues within its N-terminal cytoplasmic domain, as site-directed mutagenesis of these residues abrogated internalization and maintained the enzyme at the cell surface. Cells coexpressing these mutants and HJV produced significantly decreased levels of hepcidin compared with wild-type TMPRSS6 due to the sustained cleavage of HJV at the cell surface by TMPRSS6 mutants. Our results underscore for the first time the importance of TMPRSS6 trafficking at the plasma membrane in the regulation of hepcidin expression, an event that is essential for iron homeostasis.
Maria Domenica Cappellini - One of the best experts on this subject based on the ideXlab platform.
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The role of TMPRSS6 polymorphisms in iron deficiency anemia partially responsive to oral iron treatment.
American journal of hematology, 2015Co-Authors: Erika Poggiali, Giovanna Graziadei, Isabella Nava, Fabio Andreozzi, Dario Consonni, Maria Domenica CappelliniAbstract:Iron refractory iron deficiency anemia (IRIDA) is a rare hereditary disease caused by mutations in TMPRSS6 gene encoding Matriptase-2, a negative regulator of hepcidin transcription. Up to now, 53 IRIDA patients from 35 families with different ethnic origins have been reported and 41 TMPRSS6 mutations have been identified. TMPRSS6 polymorphisms are more frequent than mutations, and have been associated with variation in iron and hematologic parameters. Our study evaluated their presence in 113 subjects with iron deficiency anemia (IDA) partially responsive to oral iron therapy and in 50 healthy blood donors. Thalassemic trait was diagnosed in 38 patients. Sequencing analysis of TMPRSS6 gene revealed that the frequency of several polymorphisms was markedly different between IDA subjects and controls. In particular, the V736A TMPRSS6 polymorphism was associated to moderately lower hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin levels, and in thalassemia carriers with marked anemia and microcytosis. A new variant-H448R- and two uncommon polymorphisms -A719T and V795I- were also identified. These results indicate that TMPRSS6 polymorphisms are more frequent in subjects with persistent IDA than in healthy controls, and in thalassemia carriers V736A variant may account for lower hemoglobin and MCV levels. Further studies in larger court of patients are necessary to identify potential haplotypes and polymorphisms responsible for low response to oral iron treatment and may be useful for planning a correct iron supplementation.
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Does TMPRSS6 RS855791 polymorphism contribute to iron deficiency in treated celiac disease
The American journal of gastroenterology, 2015Co-Authors: Luca Elli, Isabella Nava, Erika Poggiali, Fabio Andreozzi, Domenico Girelli, Natascia Campostrini, Carolina Tomba, Maria Teresa Bardella, Dario Conte, Maria Domenica CappelliniAbstract:Does TMPRSS6 RS855791 Polymorphism Contribute to Iron Deficiency in Treated Celiac Disease?
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Genetic variability of TMPRSS6 and its association with iron deficiency anaemia
British journal of haematology, 2010Co-Authors: Paola Delbini, Valentina Vaja, Giovanna Graziadei, Lorena Duca, Isabella Nava, Chiara Refaldi, Maria Domenica CappelliniAbstract:Transmembrane Protease, Serine 6 (TMPRSS6) has an important role in iron homeostasis and its mutations, performed in TMPRSS6-deficient mice, have been recently associated with iron-refractory iron deficiency anaemia (IRIDA). Several variants of TMPRSS6 have been already identified; however the role of polymorphisms and TMPRSS6 haplotypes, causing iron deficiency anaemia, have not yet been investigated. This study sequenced the TMPRSS6 gene in 16 subjects with IRIDA phenotype and identified 27 DNA polymorphisms. Eight single nucleotide polymorphisms and four haplotypes were significantly associated with iron-refractory anaemia (P < 0·001). Our preliminary results suggest a possible association between specific haplotypes of TMPRSS6 and IRIDA.
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GENETIC VARIABILITY OF TMPRSS6 GENE AND ITS ASSOCIATION WITH IRON DEFICIENCY ANAEMIA
British Journal of Haematology, 2010Co-Authors: Paola Delbini, Valentina Vaja, Giovanna Graziadei, Lorena Duca, Isabella Nava, Chiara Refaldi, Maria Domenica CappelliniAbstract:TMPRSS6 (Transmembrane Protease, Serine 6) has an important role in iron homeostasis and its mutations, performed in TMPRSS6-deficient mice, have been recently associated with iron-refractory iron deficiency anaemia (IRIDA). Several variants of TMPRSS6 have been already identified; however the role of polymorphisms and TMPRSS6 haplotypes, causing iron deficiency anaemia, have not yet been investigated. In this study TMPRSS6 gene was sequenced in 16 subjects with IRIDA phenotype. We identified twenty-seven DNA polymorphisms. Eight SNPs and four haplotypes were significantly associated with iron-refractory anaemia (p
