scholarly journals Functional analysis of the human NRAMP family expressed in fission yeast

1999 ◽  
Vol 344 (1) ◽  
pp. 211-219 ◽  
Author(s):  
Mitsuaki TABUCHI ◽  
Tsutomu YOSHIDA ◽  
Kaoru TAKEGAWA ◽  
Fumio KISHI
Keyword(s):  
Fission Yeast ◽  
Positional Cloning ◽  
Metal Transport ◽  
Divalent Metal ◽  
Natural Resistance ◽  
Functional Difference ◽  
Transport Activity ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Macrophage Protein

The Bcg/Ity/Lsh locus in the mouse genome regulates macrophage activation for antimicrobial activity against intracellular pathogens, and the positional cloning of this locus identified the Nramp1 (natural resistance-associated macrophage protein) gene. Nramp2 was initially isolated as a homologue of Nramp1. Recently, the rat divalent metal transporter DMT1 was identified electrophysiologically, and was found to be an isoform of Nramp2, a mutation which was subsequently identified in rats suffering from hereditary iron-deficiency anaemia. Despite the 64% amino acid sequence identity of Nramp1 and Nramp2, no divalent metal transport activity has yet been detected from Nramp1, and the function of Nramp1 on the molecular level is still unclear. To investigate the divalent metal transport activity of NRAMP molecules, we constructed four chimeric NRAMP genes by swapping the domains of human NRAMP1 and NRAMP2 with each other. The functional characteristics of wild-type NRAMP1, NRAMP2 and their chimeras were determined by expression in the divalent metal transporter-disrupted strain of fission yeast, pdt1δ, and we analysed the divalent metal transport activity by complementation of the EGTA- and pH-sensitive phenotype of pdt1δ. Replacement of the N-terminal cytoplasmic domain of NRAMP2 with the NRAMP1 counterpart resulted in inactive chimeras, indicating that the functional difference between NRAMP1 and NRAMP2 is located in this region. However, results obtained with the reverse construct and other chimeras indicated that these regions are not solely responsible for the differences in EGTA- and pH-sensitivity of NRAMP1 and NRAMP2. These findings indicate that NRAMP1 itself cannot represent the divalent metal transport activity in S. pombe and the additional protein segments of the molecules located elsewhere in NRAMP1 are also functionally distinct from their NRAMP2 counterparts.

scholarly journals Parkin regulates metal transport via proteasomal degradation of the 1B isoforms of divalent metal transporter 1

2010 ◽  
Vol 113 (2) ◽  
pp. 454-464 ◽  
Author(s):  
Jerome A. Roth ◽  
Steven Singleton ◽  
Jian Feng ◽  
Michael Garrick ◽  
Prasad N. Paradkar
Keyword(s):  
Proteasomal Degradation ◽  
Metal Transport ◽  
Divalent Metal ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter

Divalent metal transporter-1 decreases metal-related injury in the lung

2005 ◽  
Vol 289 (3) ◽  
pp. L460-L467 ◽  
Author(s):  
Andrew J. Ghio ◽  
Claude A. Piantadosi ◽  
Xinchao Wang ◽  
Lisa A. Dailey ◽  
Jacqueline D. Stonehuerner ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Metal Transport ◽  
Airway Epithelial Cells ◽  
Divalent Metal ◽  
Primary Role ◽  
Airway Epithelial ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter

Exposure to airborne particulates makes the detoxification of metals a continuous challenge for the lungs. Based on the fate of iron in airway epithelial cells, we postulated that divalent metal transporter-1 (DMT1) participates in detoxification of metal associated with air pollution particles. Homozygous Belgrade rats, which are functionally deficient in DMT1, exhibited diminished metal transport from the lower respiratory tract and greater lung injury than control littermates when exposed to oil fly ash. Preexposure of normal rats to iron in vivo increased expression of the isoform of DMT1 protein that lacked an iron-response element (−IRE), accelerated metal transport out of the lung, and decreased injury after particle exposure. In contrast, normal rats preexposed to vanadium showed less expression of the −IRE isoform of DMT1, decreased metal transport, and greater pulmonary injury after particle instillation. Respiratory epithelial cells in culture gave similar results. Also, DMT1 mRNA and protein expression for the −IRE isoform increased or decreased in these cells when exposed to iron or vanadium, respectively. These results thus demonstrate for the first time a primary role for DMT1 in lung metal transport and detoxification.

Nramp1 Promotes Efficient Macrophage Recycling of Iron Following Phenylhydrazine-Induced Hemolytic Anemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 415-415
Author(s):  
Shan Soe-Lin ◽  
Bill Andriopoulos ◽  
Marc Andrews ◽  
Matthias Schranzhofer ◽  
Tanya Kahawita ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Knockout Mice ◽  
Transferrin Saturation ◽  
Divalent Metal ◽  
Natural Resistance ◽  
Mrna Levels ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Hepcidin Mrna

Abstract Natural resistance-associated macrophage protein 1 (Nramp1) is a divalent metal transporter expressed exclusively in phagocytic cells such as macrophages and neutrophils. Based on our earlier in vitro study (Soe-Lin et al. Exp Hematol.2008;36:929–937), we hypothesize that Nramp1 may participate in the recycling of iron acquired through the phagocytosis of senescent red blood cells by macrophages. In order to examine the effect of Nramp1 on iron recycling in vivo, the iron parameters of wildtype (Nramp1+/+) and Nramp1 knockout mice (Nramp1−/−) were analyzed following both acute and chronic induction of hemolytic anemia by phenylhydrazine treatment. We observe that untreated Nramp1−/− mice exhibited greater serum transferrin saturation and splenic iron content, higher duodenal ferroportin (Fpn) and divalent metal transporter 1 (DMT1) expression, and dramatically lower hepcidin mRNA levels than untreated Nramp1+/+ mice. Significant iron loading of the reticuloendothelial organs was found to increase with age in knockout mice. Following acute treatment with the hemolytic agent phenylhydrazine, Nramp1−/− mice experienced a significant decrease in serum iron levels and hematocrit, while their Nramp1+/+ counterparts were relatively unaffected. Following a month-long phenylhydrazine regimen, Nramp1−/− mice retained markedly increased quantities of iron within the liver and spleen, and exhibited greater splenomegaly and reticulocytosis than wild-type mice. Furthermore, while hepcidin mRNA levels decreased following chronic phenylhydrazine treatment in both Nramp1+/+ and Nramp1−/− mice, this effect was significantly more pronounced in Nramp1−/− mice. The data presented in this report suggest that in the absence of Nramp1, iron accumulates to a greater degree within reticuloendothelial organs such as the liver and spleen following acute and chronic hemolytic anemia. We hypothesize that the low hepcidin mRNA levels seen in Nramp1−/− mice are a response to a diminished availability of iron for erythropoiesis resulting from the aberrant increase in iron retention within their splenic reticuloendothelial macrophages. Our observation of increased DMT1 and ferroportin within the duodenums of the Nramp1−/− animals imply that the increase in transferrin saturation despite the impaired iron release from erythrophagocytosing macrophages occurs due to a compensatory increase in iron absorption from the diet. These findings are consistent with our hypothesis that Nramp1 promotes the efficient recycling of iron in erythrophagocytosing macrophages.

Both Nramp1 and Dmt1 Are Necessary for Efficient Macrophage Iron Recycling.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1994-1994
Author(s):  
Shan Soe-Lin ◽  
Sameer S Apte ◽  
Marc R Mikhael ◽  
Lidia Kayembe ◽  
Guangjun Nie ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Natural Resistance ◽  
Heme Oxygenase 1 ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Labile Iron Pool ◽  
Raw264.7 Macrophages ◽  
Macrophage Protein ◽  
Iron Pool

Abstract Abstract 1994 Poster Board I-1016 Divalent metal transporter 1 (DMT1) and natural resistance-associated macrophage protein 1 (Nramp1) are iron transporters that localize, respectively, to the early and late endosomal compartments. DMT1 is ubiquitously expressed, while Nramp1 is found only within macrophages and neutrophils. Our previous studies have identified a role for Nramp1 during macrophage erythrophagocytosis; however, little is known about the function of DMT1 during this process. Wild-type RAW264.7 macrophages (Nramp1-/-), and those stably transfected with Nramp1 (Nramp1+/+) were treated with either DMT1-siRNA, or with ebselen, a selective inhibitor of DMT1. While macrophages lacking either functional DMT1 or Nramp1 experienced a moderate reduction in iron recycling efficiency, the ability of macrophages lacking both functional DMT1 and Nramp1 to recycle hemoglobin-derived iron was severely compromised. Compared to macrophages singly deficient in either DMT1 or Nramp1 transport ability, macrophages where DMT1 and Nramp1 were both compromised exhibited an abrogated increase in labile iron pool content, released less iron, and experienced diminished upregulation of ferroportin and heme-oxygenase 1 levels following erythrophagocytosis. These results suggest that while the loss of either Nramp1 or DMT1 transport ability results in minor impairment following erythrophagocytosis, the simultaneous loss of both Nramp1 and DMT1 iron transport activity is detrimental to the iron recycling capacity of the macrophage. Disclosures: No relevant conflicts of interest to declare.

Ca2+transport activity of scallop divalent metal transporter at the concentration of seawater level

2007 ◽  
Vol 73 (3) ◽  
pp. 741-743
Author(s):  
Masaya TAKAGI ◽  
Junko TAKIYA ◽  
Kenji NAKAO ◽  
Syuji KANEKO ◽  
Haruhiko TOYOHARA
Keyword(s):  
Divalent Metal ◽  
Transport Activity ◽  
Divalent Metal Transporter ◽  
Metal Transporter

Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat

2001 ◽  
Vol 66 (6) ◽  
pp. 1198-1207 ◽  
Author(s):  
J.R. Burdo ◽  
S.L. Menzies ◽  
I.A. Simpson ◽  
L.M. Garrick ◽  
M.D. Garrick ◽  
...  
Keyword(s):  
Metal Transport ◽  
Divalent Metal ◽  
Transport Protein ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter

Hypoxia induces changes in expression of isoforms of the divalent metal transporter (DMT1) in rat pheochromocytoma (PC12) cells

2005 ◽  
Vol 69 (11) ◽  
pp. 1647-1655 ◽  
Author(s):  
Agnieszka Lis ◽  
Prasad N. Paradkar ◽  
Steve Singleton ◽  
Hung-Chieh Kuo ◽  
Michael D. Garrick ◽  
...  
Keyword(s):  
Pc12 Cells ◽  
Divalent Metal ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Pheochromocytoma Pc12 ◽  
Pheochromocytoma Pc12 Cells

scholarly journals Divalent Metal Transporter 1 Knock-Down Modulates IL-1β Mediated Pancreatic Beta-Cell Pro-Apoptotic Signaling Pathways through the Autophagic Machinery

2021 ◽  
Vol 22 (15) ◽  
pp. 8013
Author(s):  
Taewook Kang ◽  
Honggang Huang ◽  
Thomas Mandrup-Poulsen ◽  
Martin R. Larsen
Keyword(s):  
Cell Death ◽  
Divalent Metal ◽  
Β Cells ◽  
Β Cell ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Knock Down ◽  
Metal Transporter ◽  
Cell Functions ◽  
Protective Proteins

Pro-inflammatory cytokines promote cellular iron-import through enhanced divalent metal transporter-1 (DMT1) expression in pancreatic β-cells, consequently cell death. Inhibition of β-cell iron-import by DMT1 silencing protects against apoptosis in animal models of diabetes. However, how alterations of signaling networks contribute to the protective action of DMT1 knock-down is unknown. Here, we performed phosphoproteomics using our sequential enrichment strategy of mRNA, protein, and phosphopeptides, which enabled us to explore the concurrent molecular events in the same set of wildtype and DMT1-silenced β-cells during IL-1β exposure. Our findings reveal new phosphosites in the IL-1β-induced proteins that are clearly reverted by DMT1 silencing towards their steady-state levels. We validated the levels of five novel phosphosites of the potential protective proteins using parallel reaction monitoring. We also confirmed the inactivation of autophagic flux that may be relevant for cell survival induced by DMT1 silencing during IL-1β exposure. Additionally, the potential protective proteins induced by DMT1 silencing were related to insulin secretion that may lead to improving β-cell functions upon exposure to IL-1β. This global profiling has shed light on the signal transduction pathways driving the protection against inflammation-induced cell death in β-cells after DMT1 silencing.

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