Identification and characterization of a novel murine allele of Tmprss6

Bartnikas, Thomas B.; Steinbicker, Andrea U.; Campagna, Dean R.; Blevins, Sherika; Woodward, Lanette S.; Herrera, Carolina; Bloch, Kenneth D.; Justice, Monica J.; Fleming, Mark D.

doi:10.3324/haematol.2012.074617

Cited by 6 publications

(12 citation statements)

References 48 publications

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“…MT2 interacts with HJV through this region (25). Consistent with this idea, the stem region of MT2 harbors numerous IRIDA-causing mutations (34,35). Our data also suggest that the shed forms of soluble MT2 lack physiological relevance to iron homeostasis.…”

Section: Mechanistic Studies Of Matriptase-2 Activitysupporting

confidence: 82%

The catalytic, stem, and transmembrane portions of matriptase-2 are required for suppressing the expression of the iron-regulatory hormone hepcidin

Mao

Wortham

Enns

et al. 2019

Journal of Biological Chemistry

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Edited by F. Peter Guengerich Matriptase-2 (MT2) is a type-II transmembrane, trypsin-like serine protease that is predominantly expressed in the liver. It is a key suppressor for the expression of hepatic hepcidin, an ironregulatory hormone that is induced via the bone morphogenetic protein signaling pathway. A current model predicts that MT2 suppresses hepcidin expression by cleaving multiple components of the induction pathway. MT2 is synthesized as a zymogen that undergoes autocleavage for activation and shedding. However, the biologically active form of MT2 and, importantly, the contributions of different MT2 domains to its function are largely unknown. Here we examined the activities of truncated MT2 that were generated by site-directed mutagenesis or Gibson assembly master mix, and found that the stem region of MT2 determines the specificity and efficacy for substrate cleavage. The transmembrane domain allowed MT2 activation after reaching the plasma membrane, and the cytoplasmic domain facilitated these processes. Further in vivo rescue studies indicated that the entire extracellular and transmembrane domains of MT2 are required to correct the low-hemoglobin, low-serum iron, and high-hepcidin status in MT2 ؊/؊ mice. Unlike in cell lines, no autocleavage of MT2 was detected in vivo in the liver, implying that MT2 may also function independently of its proteolytic activity. In conjunction with our previous studies implicating the cytoplasmic domain as an intracellular iron sensor, these observations reveal the importance of each MT2 domain for MT2-mediated substrate cleavage and for its biological function.

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Section: Mechanistic Studies Of Matriptase-2 Activitysupporting

confidence: 82%

The catalytic, stem, and transmembrane portions of matriptase-2 are required for suppressing the expression of the iron-regulatory hormone hepcidin

Mao

Wortham

Enns

et al. 2019

Journal of Biological Chemistry

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“…Tmprss6 hem8/hem8 mice have a slightly less severe phenotype than that of Tmprss6 -/-animals. 32 Whereas there is no difference in expression of Tmprss6 mRNA in these models, 32 serum hepcidin-1 concentrations were increased only about half as much in Tmprss6 hem8/hem8 animals as they were in Tmprss6 -/-null mice ( Figure 2C,E). This observation is concordant with activity of the mutant Tmprss6 hem8 protein in vitro, where it has nearly half the enzymatic activity of the wild-type protein.…”

Section: I286fmentioning

confidence: 99%

“…This observation is concordant with activity of the mutant Tmprss6 hem8 protein in vitro, where it has nearly half the enzymatic activity of the wild-type protein. 32 The Tmprss6 hem8/-compound mutant mice have approximately the same hepcidin expression as Tmprss6 -/-animals ( Figure 2G). 32 We evaluated serum hepcidin in the Hbb th3/+ model of thalassemia intermedia and the Hfe -/-model of hereditary hemochromatosis.…”

Section: I286fmentioning

confidence: 99%

“…32 The Tmprss6 hem8/-compound mutant mice have approximately the same hepcidin expression as Tmprss6 -/-animals ( Figure 2G). 32 We evaluated serum hepcidin in the Hbb th3/+ model of thalassemia intermedia and the Hfe -/-model of hereditary hemochromatosis. In both cases, hepcidin level measured by qPCR is suppressed relative to the extent of systemic iron overload.…”

Section: I286fmentioning

confidence: 99%

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A competitive enzyme-linked immunosorbent assay specific for murine hepcidin-1: correlation with hepatic mRNA expression in established and novel models of dysregulated iron homeostasis

et al. 2014

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“…Care and characterization of BALB/cJ hpx and C57BL/6J Tmprss6 -deficient mice has been described[7, 11, 12]. Generation of hpx Hjv mice from BALB/cJ hpx and C57BL6/J Hjv mice and their characterization has been described [12].…”

Section: Methodsmentioning

confidence: 99%

Investigating the role of transferrin in the distribution of iron, manganese, copper, and zinc

2014

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The essential role of transferrin in mammalian iron metabolism is firmly established. Integral to our understanding of transferrin, studies in hpx mice, a model of inherited transferrin deficiency, have demonstrated that transferrin is essential for iron delivery for erythropoiesis and in the regulation of expression of hepcidin, a hormone that inhibits macrophage and enterocyte iron efflux. Here we investigate a potential role for transferrin in the distribution of three other physiologic metals, manganese, copper and zinc. We first assessed metal content in transferrin-rich fractions of wild-type mouse sera and demonstrate that while both iron and manganese cofractionate predominantly with transferrin, the absolute levels of manganese are several orders of magnitude lower than those of iron. We next measured metal content in multiple tissues in wild-type and hpx mice at various ages. Tissue metal imbalances were severe for iron and minimal to moderate for some metals in some tissues in hpx mice. Measurement of metal levels in a transferrin-replete yet hepcidin-deficient and iron-loaded mouse strain suggested that the observed imbalances in tissue copper, zinc and manganese levels were not all specific to hpx mice or caused directly by transferrin deficiency. Overall, our results suggest that transferrin does not have a primary role in the distribution of manganese, copper or zinc to tissues and that that the abnormalities observed in tissue manganese levels are not attributable to a direct role for transferrin in manganese metabolism but rather to an indirect effect of transferrin deficiency on hepcidin expression and/or iron metabolism.

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Identification and characterization of a novel murine allele of Tmprss6

Cited by 6 publications

References 48 publications

The catalytic, stem, and transmembrane portions of matriptase-2 are required for suppressing the expression of the iron-regulatory hormone hepcidin

The catalytic, stem, and transmembrane portions of matriptase-2 are required for suppressing the expression of the iron-regulatory hormone hepcidin

A competitive enzyme-linked immunosorbent assay specific for murine hepcidin-1: correlation with hepatic mRNA expression in established and novel models of dysregulated iron homeostasis

Investigating the role of transferrin in the distribution of iron, manganese, copper, and zinc

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