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1
Bin, Bum-Ho, Juyeon Seo et Sung Tae Kim. « Function, Structure, and Transport Aspects of ZIP and ZnT Zinc Transporters in Immune Cells ». Journal of Immunology Research 2018 (2 octobre 2018) : 1–9. http://dx.doi.org/10.1155/2018/9365747.
Texte intégralRésumé :
Zinc is an important trace metal in immune systems, and zinc transporters are involved in many immune responses. Recent advances have revealed the structural and biochemical bases for zinc transport across the cell membrane, with clinical implications for the regulation of zinc homeostasis in immune cells like dendritic cells, T cells, B cells, and mast cells. In this review, we discuss the function, structure, and transport aspects of two major mammalian zinc transporter types, importers and exporters. First, Zrt-/Irt-like proteins (ZIPs) mediate the zinc influx from the extracellular or luminal side into the cytoplasm. There are 14 ZIP family members in humans. They form a homo- or heterodimer with 8 transmembrane domains and extra-/intracellular domains of various lengths. Several ZIP members show specific extracellular domains composed of two subdomains, a helix-rich domain and proline-alanine-leucine (PAL) motif-containing domain. Second, ZnT (zinc transporter) was initially identified in early studies of zinc biology; it mediates zinc efflux as a counterpart of ZIPs in zinc homeostasis. Ten family members have been identified. They show a unique architecture characterized by a Y-shaped conformation and a large cytoplasmic domain. A precise, comprehensive understanding of the structures and transport mechanisms of ZIP and ZnT in combination with mice experiments would provide promising drug targets as well as a basis for identifying other transporters with therapeutic potential.
2
Satarug, Soisungwan, Scott H. Garrett, Seema Somji, Mary Ann Sens et Donald A. Sens. « Aberrant Expression of ZIP and ZnT Zinc Transporters in UROtsa Cells Transformed to Malignant Cells by Cadmium ». Stresses 1, no 2 (22 avril 2021) : 78–89. http://dx.doi.org/10.3390/stresses1020007.
Texte intégralRésumé :
Maintenance of zinc homeostasis is pivotal to the regulation of cell growth, differentiation, apoptosis, and defense mechanisms. In mammalian cells, control of cellular zinc homeostasis is through zinc uptake, zinc secretion, and zinc compartmentalization, mediated by metal transporters of the Zrt-/Irt-like protein (ZIP) family and the Cation Diffusion Facilitators (CDF) or ZnT family. We quantified transcript levels of ZIP and ZnT zinc transporters expressed by non-tumorigenic UROtsa cells and compared with those expressed by UROtsa clones that were experimentally transformed to cancer cells by prolonged exposure to cadmium (Cd). Although expression of the ZIP8 gene in parent UROtsa cells was lower than ZIP14 (0.1 vs. 83 transcripts per 1000 β-actin transcripts), an increased expression of ZIP8 concurrent with a reduction in expression of one or two zinc influx transporters, namely ZIP1, ZIP2, and ZIP3, were seen in six out of seven transformed UROtsa clones. Aberrant expression of the Golgi zinc transporters ZIP7, ZnT5, ZnT6, and ZnT7 were also observed. One transformed clone showed distinctively increased expression of ZIP6, ZIP10, ZIP14, and ZnT1, with a diminished ZIP8 expression. These data suggest intracellular zinc dysregulation and aberrant zinc homeostasis both in the cytosol and in the Golgi in the transformed UROtsa clones. These results provide evidence for zinc dysregulation in transformed UROtsa cells that may contribute in part to their malignancy and/or muscle invasiveness.
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Becares, Eva Ramos, Per Amstrup Pedersen, Pontus Gourdon et Kamil Gotfryd. « Overproduction of Human Zip (SLC39) Zinc Transporters in Saccharomyces cerevisiae for Biophysical Characterization ». Cells 10, no 2 (21 janvier 2021) : 213. http://dx.doi.org/10.3390/cells10020213.
Texte intégralRésumé :
Zinc constitutes the second most abundant transition metal in the human body, and it is implicated in numerous cellular processes, including cell division, DNA and protein synthesis as well as for the catalytic activity of many enzymes. Two major membrane protein families facilitate zinc homeostasis in the animal kingdom, i.e., Zrt/Irt-like proteins (ZIPs aka solute carrier 39, SLC39, family) and Zn transporters (ZnTs), essentially conducting zinc flux in the opposite directions. Human ZIPs (hZIPs) regulate import of extracellular zinc to the cytosol, being critical in preventing overaccumulation of this potentially toxic metal, and crucial for diverse physiological and pathological processes, including development of neurodegenerative disorders and several cancers. To date, our understanding of structure–function relationships governing hZIP-mediated zinc transport mechanism is scarce, mainly due to the notorious difficulty in overproduction of these proteins for biophysical characterization. Here we describe employment of a Saccharomyces cerevisiae-based platform for heterologous expression of hZIPs. We demonstrate that yeast is able to produce four full-length hZIP members belonging to three different subfamilies. One target (hZIP1) is purified in the high quantity and homogeneity required for the downstream biochemical analysis. Our work demonstrates the potential of the described production system for future structural and functional studies of hZIP transporters.
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Kambe, Taiho, Jim Geiser, Brett Lahner, David E. Salt et Glen K. Andrews. « Slc39a1 to 3 (subfamily II) Zip genes in mice have unique cell-specific functions during adaptation to zinc deficiency ». American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 294, no 5 (mai 2008) : R1474—R1481. http://dx.doi.org/10.1152/ajpregu.00130.2008.
Texte intégralRésumé :
Subfamily II of the solute carrier (Slc)39a family contains three highly conserved members (ZIPs 1–3) that share a 12-amino acid signature sequence present in the putative fourth transmembrane domain and function as zinc transporters in transfected cells. The physiological significance of this genetic redundancy is unknown. Here we report that the complete elimination of all three of these Zip genes, by targeted mutagenesis and crossbreeding mice, causes no overt phenotypic effect. When mice were fed a zinc-adequate diet, several indicators of zinc status were indistinguishable between wild-type and triple-knockout mice, including embryonic morphogenesis and growth, alkaline phosphatase activity in the embryo, ZIP4 protein in the visceral yolk sac, and initial rates (30 min) of accumulation/retention of 67Zn in liver and pancreas. When mice were fed a zinc-deficient diet, embryonic membrane-bound alkaline phosphatase activity was reduced to a much greater extent, and 80% of the embryos of the triple-knockout mice developed abnormally compared with 12% of the embryos of wild-type mice. During zinc deficiency, the accumulation/retention (3 h) of 67Zn in the liver and pancreas of weanlings was significantly impaired in the triple-knockout mice compared with wild-type mice. Thus none of these three mammalian Zip genes apparently plays a critical role in zinc homeostasis when zinc is replete, but they play important, noncompensatory roles when this metal is deficient.
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Figueira, Antonio, Ederson Akio Kido et Raul Santin Almeida. « Identifying sugarcane expressed sequences associated with nutrient transporters and peptide metal chelators ». Genetics and Molecular Biology 24, no 1-4 (décembre 2001) : 207–20. http://dx.doi.org/10.1590/s1415-47572001000100028.
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Plant nutrient uptake is an active process, requiring energy to accumulate essential elements at higher levels in plant tissues than in the soil solution, while the presence of toxic metals or excess of nutrients requires mechanisms to modulate the accumulation of ions. Genes encoding ion transporters isolated from plants and yeast were used to identify sugarcane putative homologues in the sugarcane expressed sequence tag (SUCEST) database. Five cluster consensi with sequence homology to plant high-affinity phosphate transporter genes were identified. One cluster consensus allowed the prediction of a full-length protein containing 541 amino acids, with 81% amino acid identity to the Nicotiana tabacum NtPT1 gene, consisting of 12 membrane-spanning domains divided by a large hydrophilic charged region. Putative homologues to Arabidopsis thaliana micronutrient transporter genes were also detected in some of the SUCEST libraries. Iron uptake in grasses involves the release of the phytosiderophore mugeneic acid (MA) which chelate Fe3+ which is then absorbed by a specific transporter. Sugarcane expressed sequence tag (EST) homologous to genes coding for three enzymes of the mugeneic acid biosynthetic pathway [nicotianamine synthase; nicotianamine transferase; and putative mugeneic acid synthetase (ids3)] and a putative Fe3+-phytosiderophore transporter were detected. Seven sugarcane sequence clusters were identified with strong homology to members of the ZIP gene family (ZIP1, ZIP3, ZIP4, IRT1 and ZNT1), while four clusters homologous to ZIP2 and three to ZAT were found. Homologues to members of another gene family, Nramp, which code for broad-specificity transition metal transporters were also detected with constitutive expression. Partial transcripts homologous to genes encoding gamma-glutamylcysteine synthetase, glutathione synthetase, and phytochelatin synthase (responsible for biosynthesis of the metal chelator phytochelatin) and all four types of the major plant metal-chelator peptide metallothionein (MT) were identified: Type I MT being the most abundant (>1% of seed-library reads), followed by Type II which had a similar pattern of expression as that described for Arabidopsis MT. Identifying and understanding the expression of genes associated with nutrient uptake and metal tolerance could lead to the development of more nutrient-efficient sugarcane cultivars, or might allow the use of sugarcane as a hyper-accumulator plant for the restoration of contaminated areas in phytoremediation programs.
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Satarug, Soisungwan, David A. Vesey et Glenda C. Gobe. « The Evolving Role for Zinc and Zinc Transporters in Cadmium Tolerance and Urothelial Cancer ». Stresses 1, no 2 (19 mai 2021) : 105–18. http://dx.doi.org/10.3390/stresses1020009.
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Cadmium (Cd) is an environmental toxicant with serious public health consequences due to its persistence within arable soils, and the ease with which it enters food chains and then, accumulates in human tissues to induce a broad range of adverse health effects. The present review focuses on the role of zinc (Zn), a nutritionally essential metal, to protect against the cytotoxicity and carcinogenicity of Cd in urinary bladder epithelial cells. The stress responses and defense mechanisms involving the low-molecular-weight metal binding protein, metallothionein (MT), are highlighted. The efflux and influx transporters of the ZnT and Zrt-/Irt-like protein (ZIP) gene families are discussed with respect to their putative role in retaining cellular Zn homeostasis. Among fourteen ZIP family members, ZIP8 and ZIP14 mediate Cd uptake by cells, while ZnT1 is among ten ZnT family members solely responsible for efflux of Zn (Cd), representing cellular defense against toxicity from excessively high Zn (Cd) intake. In theory, upregulation of the efflux transporter ZnT1 concomitant with the downregulation of influx transporters such as ZIP8 and ZIP14 can prevent Cd accumulation by cells, thereby increasing tolerance to Cd toxicity. To link the perturbation of Zn homeostasis, reflected by the aberrant expression of ZnT1, ZIP1, ZIP6, and ZIP10, with malignancy, tolerance to Cd toxicity acquired during Cd-induced transformation of a cell model of human urothelium, UROtsa, is discussed as a particular example.
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Cousins, Robert J. « Gastrointestinal Factors Influencing Zinc Absorption and Homeostasis ». International Journal for Vitamin and Nutrition Research 80, no 45 (1 octobre 2010) : 243–48. http://dx.doi.org/10.1024/0300-9831/a000030.
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Diet-derived luminal factors have a major influence on zinc available for uptake across the apical membrane of enterocytes. Malabsorption and possibly intestinal microbiota limit this zinc availability. The transporter ZIP4 is expressed along the entire gastrointestinal tract and acts as a major processor of dietary zinc for loading into enterocytes from the apical membrane. Zip4 and other Zip family genes expressed in the gastrointestinal tract are up-regulated in periods of dietary zinc restriction. This provides for powerful homeostatic control. The transporter ZIP14 is up-regulated along the entire gastrointestinal tract by proinflammatory conditions. Intracellular transporters such as ZnT7, influence the transcellular movement of zinc across the enterocyte. Metallothionein, an intracellular metal buffer, and the transporter ZnT1 at the basolateral membrane, regulate the amount of zinc released to the portal circulation for systemic distribution. Pancreatic release of zinc by acinar cells is through the secretory process and apical membrane and involves transporters ZnT2 and ZnT1, respectively. Expression of both transporters is zinc-responsive. Enterocytes and acinar cells constitutively express Zip5 at the basolateral membrane, where it may serve as a monitor of zinc status.
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Chen, Shu-Wei, Kun Wu, Wu-Hong Lv, Fang Chen, Chang-Chun Song et Zhi Luo. « Functional Analysis of Two Zinc (Zn) Transporters (ZIP3 and ZIP8) Promoters and Their Distinct Response to MTF1 and RREB1 in the Regulation of Zn Metabolism ». International Journal of Molecular Sciences 21, no 17 (26 août 2020) : 6135. http://dx.doi.org/10.3390/ijms21176135.
Texte intégralRésumé :
ZIP (zinc-regulated transporters, iron-regulated transporter-like protein) family plays an important role in organism Zn balance. This research identified the promoter regions of ZIP3 and ZIP8, two members of ZIP family, from a freshwater teleost yellow catfish Pelteobagrus fulvidraco, characterized the binding sequences of the metal-responsive transcription factor-1 (MTF-1) and Ras responsive element binding protein 1 (RREB1) on their promoter regions. The present study cloned and obtained the 2027 bp of ZIP3 promoter and 1664 bp of ZIP8 promoter, and predicted several key elements on their promoters, such as the binding sites of CREB (cAMP-response element binding protein), KLF4 (Kruppel like factor 4), MTF-1 and RREB1. The sequence deletion from −361 bp to −895 bp down-regulated the luciferase activity of ZIP3 promoter, and the deletion from −897 bp to −1664 bp down-regulated the luciferase activity of ZIP8 promoter. Within different deletion plasmids, the relative luciferase activities of ZIP3 and ZIP8 promoters changes to Zn incubation in a Zn concentration-dependent manner. The site mutagenesis and EMSA (electrophoretic mobility shift assay) found that the −1327 bp/−1343 bp MTF-1 binding site and the −248 bp/−267 bp RREB1 binding site on the ZIP3 promoter, and the −1543 bp/−1557 bp MTF-1 binding site on the ZIP8 promoter are functional sites. Low Zn increased the binding capability between MTF-1 and its responsive site on the ZIP3 promoter, and high Zn increased the transcriptional activation ZIP3 by RREB1; Zn also promoted the binding ability between MTF-1 and its responsive element on the ZIP8 promoter. This study provides the first direct evidence for the response elements of MTF-1 and RREB1 on ZIP3 and MTF-1 on ZIP8 to Zn, which are very important for the evaluation of Zn nutrition and toxicity in vertebrates.
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Kim, Juyoung, Jaekwon Lee et Moon-Suhn Ryu. « Zinc and the Zinc Transporter SLC39A10/ZIP10 Are Required for Heme Synthesis in Developing Erythroid Progenitors ». Current Developments in Nutrition 5, Supplement_2 (juin 2021) : 1320. http://dx.doi.org/10.1093/cdn/nzab059_021.
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Abstract Objectives Zinc is an essential nutrient for diverse biological processes in the body. Cellular zinc homeostasis is established through differential expressions of the transmembrane zinc transporter proteins, ZnTs and ZIPs. The aims of the current studies were to elucidate the roles of cellular zinc in erythrocyte maturation, and to determine the zinc transporters essential to erythroid zinc homeostasis. Methods G1E-ER4 mouse cells were employed as an in vitro study model of terminal erythroid differentiation. A cell-impermeable zinc chelator, diethylenetriamine pentaacetate (DTPA), was used to limit extracellular zinc availability. For gene silencing, gene-specific siRNAs were introduced to cells via Nucleofection. Functional impacts of zinc and gene deficiency were assessed via ICP-MS-based metal quantitation, heme assays, and gene expression assays using RNA-seq, qPCR, and western analyses. Results G1E-ER4 cells featured a 1.7-fold increase in total cellular zinc contents after 48 h of differentiation. Restriction of zinc import by 50 µM of DTPA led to less red coloration and lower increases in mean corpuscular hemoglobin contents by development. The heme deficiency by DTPA was fully restored by the addition of equimolar zinc, and was not due to changes in cellular iron contents. Zinc-deficient G1E-ER4 cells differentiated with normal Alas2 and Hbb-b1 transcript responses, but less Alad and alpha-globin expressions. Among the 24 zinc transporter genes, Zip10 produced the most prominent response to zinc restriction in differentiating erythroid cells. ZIP10-deficient G1E-ER4 cells were less efficient than control cells in hemoglobin production under zinc restriction. ZIP10 deficiency alone had no effects on the molecular indices of red cell hemoglobinization. Conclusions Our studies characterize zinc as a nutrient essential to normal erythroid maturation and heme synthesis. Moreover, we have identified a compensatory role of ZIP10 for erythroid zinc homeostasis during zinc restriction. Thus, poor zinc status and ZIP10 mutations might serve as potential risk factors and thus new therapeutic targets for anemia and other erythrocyte-related disorders. Funding Sources Supported by CFANS Graduate Fellowship to JK, and the Allen Foundation, Inc. and USDA NIFA Hatch Funds to M-SR.
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Gebeyew, Kefyalew, Chunyu Jiang, Qinghua Gao, Liping Zhang, Hanhua Zhu, Yushi Tian, Qi Wang, Yuqing Wei, Zhiliang Tan et Xuefeng Han. « Cadmium Accumulation in the Goat Liver and Kidney Is Partially Promoted by the Upregulation of Metal Transporter Genes ». Animals 12, no 11 (30 mai 2022) : 1408. http://dx.doi.org/10.3390/ani12111408.
Texte intégralRésumé :
Metal transporters, including divalent metal-ion transporter-1 (DMT1), Zrt-/Irt-like protein 8 and 14 (ZIP8 and ZIP14), and ferroportin-1 (FPN1), reportedly participate in cellular cadmium (Cd) uptake, but those in farm animals remain unclarified. This study aimed to examine the growth, plasma biochemical indices, Cd accumulation, and expression of metal transporter genes in the liver, kidney, and muscle of goats exposed to rice paddies contaminated with different levels of Cd. Twenty-four goats were randomly assigned across three dietary treatments: 0.23, 0.63, and 1.07 mg of Cd/kg of dry matter (DM) for 60 days. The results showed that dietary Cd exposure increased (p < 0.05) both Cd accumulation and the mRNA expressions of metal transporter genes (DMT1, ZIP, and FPN1) in the liver and kidney but not in the muscle, suggesting dietary Cd exhibited different deposition rates between goat liver, kidney, and muscle. These outcomes suggest that high levels of dietary Cd stimulated the expression of metal transporter genes and thereby enhanced the uptake and accumulation of Cd in the goat liver and kidney. As such, higher Cd concentrations in the liver and kidney observed with Cd diets could be partly explained by upregulation of metal transport genes expression.
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Shafiq, Sarfraz, Asim Ali, Yasar Sajjad, Qudsia Zeb, Muhammad Shahzad, Abdul Rehman Khan, Rashid Nazir et Emilie Widemann. « The Interplay between Toxic and Essential Metals for Their Uptake and Translocation Is Likely Governed by DNA Methylation and Histone Deacetylation in Maize ». International Journal of Molecular Sciences 21, no 18 (22 septembre 2020) : 6959. http://dx.doi.org/10.3390/ijms21186959.
Texte intégralRésumé :
The persistent nature of lead (Pb) and cadmium (Cd) in the environment severely affects plant growth and yield. Conversely, plants acquire zinc (Zn) from the soil for their vital physiological and biochemical functions. However, the interplay and coordination between essential and toxic metals for their uptake and translocation and the putative underlying epigenetic mechanisms have not yet been investigated in maize. Here, we report that the presence of Zn facilitates the accumulation and transport of Pb and Cd in the aerial parts of the maize plants. Moreover, the Zn, Pb, and Cd interplay specifically interferes with the uptake and translocation of other divalent metals, such as calcium and magnesium. Zn, Pb, and Cd, individually and in combinations, differentially regulate the expression of DNA methyltransferases, thus alter the DNA methylation levels at the promoter of Zinc-regulated transporters, Iron-regulated transporter-like Protein (ZIP) genes to regulate their expression. Furthermore, the expression of histone deacetylases (HDACs) varies greatly in response to individual and combined metals, and HDACs expression showed a negative correlation with ZIP transporters. Our study highlights the implication of DNA methylation and histone acetylation in regulating the metal stress tolerance dynamics through Zn transporters and warns against the excessive use of Zn fertilizers in metal contaminated soils.
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Bằng, Cao Phi. « Metal transporter encoding gene families in Fabaceae : III. The zinc-iron permease (ZIP) gene family ». Science and Technology Development Journal - Natural Sciences 4, no 1 (4 avril 2020) : First. http://dx.doi.org/10.32508/stdjns.v4i1.690.
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In plants, Zinc and Iron are transported through the membrane by proteins belonging to Zinc-Iron permease (ZIP: ZRT/IRT-like Protein). In this work, the ZIP gene families were identified in the genome of five legume species. The results demonstrated that the ZIPs were belonged to a multigeneic family in each species including soybean (28 genes), Medicago truncalata (16 genes), chickpea (7 genes), pigeon pea (12 genes), and Lotus japonicus (15 genes). Each gene contained from one to twelve introns. ZIP proteins possessed a conserved histidine-rich motif. Most of these proteins contained eight putative transmembrane domains and were predicted to be localized in plasma membranes. The phylogeny analysis showed that the legume ZIPs were classified into four main groups, each of which includes many subgroups. The group I contained the ZIP members of five examined plants. Moreover, the phylogeny showed gene gain events (expansion) in group I and gene loss events in other groups. The gene expansion in group I is likely to have arisen mainly from recent duplication events of ZIP genes in the examined legume plants, after specialization. The expression analysis showed that all of ZIP genes were expressed in all of the examined tissues in L. japonicus. The expression level of ZIP members was not similar in different tissues of the plant. Some ZIP genes were predominantly expressed in certain tissues for most of the legume species investigated.
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Gyimesi, Gergely, Giuseppe Albano, Daniel G. Fuster, Matthias A. Hediger et Jonai Pujol-Giménez. « Unraveling the structural elements of pH sensitivity and substrate binding in the human zinc transporter SLC39A2 (ZIP2) ». Journal of Biological Chemistry 294, no 20 (26 mars 2019) : 8046–63. http://dx.doi.org/10.1074/jbc.ra118.006113.
Texte intégralRésumé :
The transport and ion-coupling mechanisms of ZIP transporters remain largely uncharacterized. Previous work in our laboratory has revealed that the solute carrier family 39 member A2 (SLC39A2/ZIP2) increases its substrate transport rate in the presence of extracellular H+. Here, we used a combination of in silico and in vitro techniques involving structural modeling, mutagenesis, and functional characterization in HEK293 cells to identify amino acid residues potentially relevant for both the ZIP2–H+ interaction and substrate binding. Our ZIP2 models revealed a cluster of charged residues close to the substrate–translocation pore. Interestingly, the H63A substitution completely abrogated pH sensitivity, and substitutions of Glu-67 and Phe-269 altered the pH and voltage modulation of transport. In contrast, substitution of Glu-106, which might be part of a dimerization interface, altered pH but not voltage modulation. Substitution of Phe-269, located close to the substrate-binding site, also affected substrate selectivity. These findings were supported by an additional model of ZIP2 that was based on the structure of a prokaryotic homolog, Bordetella bronchiseptica ZrT/Irt-like protein (bbZIP), and in silico pKa calculations. We also found that residues Glu-179, His-175, His-202, and Glu-276 are directly involved in the coordination of the substrate metal ion. We noted that, unlike bbZIP, human ZIP2 is predicted to harbor a single divalent metal-binding site, with the charged side chain of Lys-203 replacing the second bound ion. Our results provide the first structural evidence for the previously observed pH and voltage modulation of ZIP2-mediated metal transport, identify the substrate-binding site, and suggest a structure-based transport mechanism for the ZIP2 transporter.
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Grass, Gregor, Sylvia Franke, Nadine Taudte, Dietrich H. Nies, Lisa M. Kucharski, Michael E. Maguire et Christopher Rensing. « The Metal Permease ZupT from Escherichia coli Is a Transporter with a Broad Substrate Spectrum ». Journal of Bacteriology 187, no 5 (1 mars 2005) : 1604–11. http://dx.doi.org/10.1128/jb.187.5.1604-1611.2005.
Texte intégralRésumé :
ABSTRACT The Escherichia coli zupT (formerly ygiE) gene encodes a cytoplasmic membrane protein (ZupT) related to members of the eukaryotic ZIP family of divalent metal ion transporters. Previously, ZupT was shown to be responsible for uptake of zinc. In this study, we show that ZupT is a divalent metal cation transporter of broad substrate specificity. An E. coli strain with a disruption in all known iron uptake systems could grow in the presence of chelators only if zupT was expressed. Heterologous expression of Arabidopsis thaliana ZIP1 could also alleviate iron deficiency in this E. coli strain, as could expression of indigenous mntH or feoABC. Transport studies with intact cells showed that ZupT facilitates uptake of 55Fe2+ similarly to uptake of MntH or Feo. Other divalent cations were also taken up by ZupT, as shown using 57Co2+. Expression of zupT rendered E. coli cells hypersensitive to Co2+ and sensitive to Mn2+. ZupT did not appear to be metal regulated: expression of a Φ(zupT-lacZ) operon fusion indicated that zupT is expressed constitutively at a low level.
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Scheiber, Ivo F., Neftali Ortega Alarcon et Ningning Zhao. « Manganese Uptake by A549 Cells is Mediated by Both ZIP8 and ZIP14 ». Nutrients 11, no 7 (28 juin 2019) : 1473. http://dx.doi.org/10.3390/nu11071473.
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The alveolar epithelia of the lungs require manganese (Mn) as an essential nutrient, but also provide an entry route for airborne Mn that can cause neurotoxicity. Transporters involved in Mn uptake by alveolar epithelial cells are unknown. Recently, two members of the Zrt- and Irt-like protein (ZIP) family of metal transporters, ZIP8 and ZIP14, have been identified as crucial Mn importers in vivo. ZIP8 is by far most abundantly expressed in the lungs, whereas ZIP14 expression in the lungs is low compared to other tissues. We hypothesized that Mn uptake by alveolar epithelial cells is primarily mediated by ZIP8. To test our hypothesis, we used A549 cells, a type II alveolar cell line. Mirroring the in vivo situation, A549 cells expressed higher levels of ZIP8 than cell models for the liver, intestines, and kidney. Quantification of ZIP8 and ZIP14 revealed a strong enrichment of ZIP8 over ZIP14 in A549 cells. Using siRNA technology, we identified ZIP8 and ZIP14 as the major transporters mediating Mn uptake by A549 cells. To our surprise, knockdown of either ZIP8 or ZIP14 impaired Mn accumulation to a similar extent, which we traced back to similar amounts of ZIP8 and ZIP14 at the plasma membrane. Our study highlights the importance of both ZIP8 and ZIP14 in Mn metabolism of alveolar epithelial cells.
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Shi, Yisu, Qiaonan Zhang, Lei Wang, Qiuxia Du, Michael Ackah, Peng Guo, Danyan Zheng, Mengmeng Wu et Weiguo Zhao. « Functional Characterization of MaZIP4, a Gene Regulating Copper Stress Tolerance in Mulberry (Morus atropurpurea R.) ». Life 12, no 9 (26 août 2022) : 1311. http://dx.doi.org/10.3390/life12091311.
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ZIP4 (zinc transporter 4) plays important roles in transporting Cu2+ ions in plants, which may contribute to the maintenance of plant metal homeostasis in growth, plant development and normal physiological metabolism. However, ZIP4 transporters have not been described in mulberry and the exact function of ZIP4 transporters in regulating the homeostasis of Cu in mulberry remains unclear. In this study, a new ZIP4 gene (MaZIP4) was isolated and cloned from Morus atropurpurea R. Phylogenetic analysis of amino sequences suggested that the amino-acid sequence of the MaZIP4 protein shows high homology with other ZIP4 proteins of Morus notabilis, Trema orientale, Ziziphus jujube and Cannabis sativa. In addition, a MaZIP4 silenced line was successfully constructed using virus-induced gene silencing (VIGS). The analysis of MaZIP4 expression by quantitative real-time PCR in mulberry showed that the level of MaZIP4 expression increased with increasing Cu concentration until the Cu concentration reached 800 ppm. Relative to the blank (WT) and the negative controls, malondialdehyde (MDA) levels increased significantly and rose with increasing Cu concentration in the MaZIP4 silenced line, whereas the soluble protein and proline content, superoxide dismutase (SOD) and peroxidase (POD) activities of these transgenic plants were lower. These results indicated that MaZIP4 may play an important role in the resistance of mulberry to Cu stress.
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Tao, Jingyu, et Lingli Lu. « Advances in Genes-Encoding Transporters for Cadmium Uptake, Translocation, and Accumulation in Plants ». Toxics 10, no 8 (22 juillet 2022) : 411. http://dx.doi.org/10.3390/toxics10080411.
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Cadmium (Cd) is a heavy metal that is highly toxic for plants, animals, and human beings. A better understanding of the mechanisms involved in Cd accumulation in plants is beneficial for developing strategies for either the remediation of Cd-polluted soils using hyperaccumulator plants or preventing excess Cd accumulation in the edible parts of crops and vegetables. As a ubiquitous heavy metal, the transport of Cd in plant cells is suggested to be mediated by transporters for essential elements such as Ca, Zn, K, and Mn. Identification of the genes encoding Cd transporters is important for understanding the mechanisms underlying Cd uptake, translocation, and accumulation in either crop or hyperaccumulator plants. Recent studies have shown that the transporters that mediate the uptake, transport, and accumulation of Cd in plants mainly include members of the natural resistance-associated macrophage protein (Nramp), heavy metal-transporting ATPase (HMA), zinc and iron regulated transporter protein (ZIP), ATP-binding cassette (ABC), and yellow stripe-like (YSL) families. Here, we review the latest advances in the research of these Cd transporters and lay the foundation for a systematic understanding underlying the molecular mechanisms of Cd uptake, transport, and accumulation in plants.
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Zhang, Tuo, Eziz Kuliyev, Dexin Sui et Jian Hu. « The histidine-rich loop in the extracellular domain of ZIP4 binds zinc and plays a role in zinc transport ». Biochemical Journal 476, no 12 (28 juin 2019) : 1791–803. http://dx.doi.org/10.1042/bcj20190108.
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Abstract The Zrt-/Irt-like protein (ZIP) family mediates zinc influx from extracellular space or intracellular vesicles/organelles, playing a central role in systemic and cellular zinc homeostasis. Out of the 14 family members encoded in human genome, ZIP4 is exclusively responsible for zinc uptake from dietary food and dysfunctional mutations of ZIP4 cause a life-threatening genetic disorder, Acrodermatitis Enteropathica (AE). About half of the missense AE-causing mutations occur within the large N-terminal extracellular domain (ECD), and our previous study has shown that ZIP4–ECD is crucial for optimal zinc uptake but the underlying mechanism has not been clarified. In this work, we examined zinc binding to the isolated ZIP4–ECD from Pteropus Alecto (black fruit bat) and located zinc-binding sites with a low micromolar affinity within a histidine-rich loop ubiquitously present in ZIP4 proteins. Zinc binding to this protease-susceptible loop induces a small and highly localized structural perturbation. Mutagenesis and functional study on human ZIP4 by using an improved cell-based zinc uptake assay indicated that the histidine residues within this loop are not involved in preselection of metal substrate but play a role in promoting zinc transport. The possible function of the histidine-rich loop as a metal chaperone facilitating zinc binding to the transport site and/or a zinc sensor allosterically regulating the transport machinery was discussed. This work helps to establish the structure/function relationship of ZIP4 and also sheds light on other metal transporters and metalloproteins with clustered histidine residues.
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Fasani, Elisa, Giovanni DalCorso, Gianluca Zorzi, Caterina Agrimonti, Rosaria Fragni, Giovanna Visioli et Antonella Furini. « Overexpression of ZNT1 and NRAMP4 from the Ni Hyperaccumulator Noccaea caerulescens Population Monte Prinzera in Arabidopsis thaliana Perturbs Fe, Mn, and Ni Accumulation ». International Journal of Molecular Sciences 22, no 21 (2 novembre 2021) : 11896. http://dx.doi.org/10.3390/ijms222111896.
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Metalliferous soils are characterized by a high content of metal compounds that can hamper plant growth. The pseudometallophyte Noccaea caerulescens is able to grow on metalliferous substrates by implementing both tolerance and accumulation of usually toxic metal ions. Expression of particular transmembrane transporter proteins (e.g., members of the ZIP and NRAMP families) leads to metal tolerance and accumulation, and its comparison between hyperaccumulator N. caerulescens with non-accumulator relatives Arabidopsis thaliana and Thlaspi arvense has deepened our knowledge on mechanisms adopted by plants to survive in metalliferous soils. In this work, two transporters, ZNT1 and NRAMP4, expressed in a serpentinic population of N. caerulescens identified on the Monte Prinzera (Italy) are considered, and their expression has been induced in yeast and in A. thaliana. In the latter, single transgenic lines were crossed to test the effect of the combined over-expression of the two transporters. An enhanced iron and manganese translocation towards the shoot was induced by overexpression of NcZNT1. The combined overexpression of NcZNT1 and NcNRAMP4 did perturb the metal accumulation in plants.
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Guerinot, Mary Lou. « The ZIP family of metal transporters ». Biochimica et Biophysica Acta (BBA) - Biomembranes 1465, no 1-2 (mai 2000) : 190–98. http://dx.doi.org/10.1016/s0005-2736(00)00138-3.
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Wei, Guojun, Yuze Wu et Ningning Zhao. « Generation of a Polyclonal Antibody against the Mouse Metal Transporter ZIP8 ». Antibodies 10, no 2 (21 avril 2021) : 16. http://dx.doi.org/10.3390/antib10020016.
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ZIP8 is a newly identified metal transporter. In human patients, mutations in ZIP8 result in severe manganese deficiency, suggesting a critical role for ZIP8 in regulating systemic manganese homeostasis. In mice, the deletion of ZIP8 recapitulates the symptoms of patients with ZIP8 mutations. However, further studies using mouse models to examine ZIP8′s function were hindered by the lack of suitable antibodies to detect endogenous ZIP8 protein. In this study, we report the design, generation, and validation of a polyclonal antibody against mouse ZIP8. We have demonstrated that the newly generated antibody can be reliably used in immunoblotting analysis to detect endogenous ZIP8 protein in mouse tissues. The successful generation and validation of anti-mouse ZIP8 antibody provide opportunities to further examine the function and regulation of this metal transporter. In addition, our study may provide valuable insights into the future development of antibodies targeting polytopic membrane proteins.
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Knutson, Mitchell. « Non-Transferrin-Mediated Iron Delivery ». Blood 128, no 22 (2 décembre 2016) : SCI—22—SCI—22. http://dx.doi.org/10.1182/blood.v128.22.sci-22.sci-22.
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Abstract In iron overload conditions such as thalassemia major and hereditary hemochromatosis, the iron-carrying capacity of plasma transferrin is exceeded, giving rise to non-transferrin-bound iron (NTBI). NTBI is taken up preferentially by the liver, and to a lesser extent, the kidney, pancreas, and heart. How NTBI is taken up by various tissues has been elusive. We recently demonstrated that the plasma membrane metal-ion transporter SLC39A14 (ZIP14) mediates NTBI uptake and iron loading of the liver and pancreas, but not the kidney, heart or most other tissues¹ Given that the heart is particularly susceptible to iron-related toxicity, we are currently investigating the contribution of other iron transporters to iron loading of this organ. Possible alternative cardiac iron importers include L-type and T-type calcium channels, divalent metal transporter 1 (DMT1), and SLC39A8 (ZIP8). To examine the role of DMT1 and ZIP8 in cardiac iron metabolism, we generated mice with cardiomyocyte-specific disruption of DMT1 (Dmt1heart/heart) or ZIP8 (Zip8heart/heart). The mice were then crossed with hemojuvelin knockout (Hjv-/-) mice, a model of juvenile hemochromatosis characterized by high circulating levels of NTBI. Dmt1heart/heart mice were found to have cardiac non-heme iron concentrations that were 30% lower (P<0.01) than those of wild-type littermate controls at 6 weeks of age. Interestingly, however, double mutant Hjv-/-; Dmt1heart/heart mice accumulated more cardiac non-heme iron (3.9X control) than did single-mutant Hjv-/- mice (2.3X control) at 6 weeks of age. Cardiac-specific disruption of Zip8 did not affect cardiac non-heme iron concentrations under basal conditions or when mice were crossed with Hjv-/- mice. Collectively, these data indicate that DMT1 and ZIP8 are dispensable for iron loading of the heart in a mouse model of hemochromatosis. Our data additionally suggest that DMT1 may play a role in normal cardiac iron metabolism. Reference:Jenkitkasemwong S, Wang C, Coffey R, et al. SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis.Cell Metabolism.2015; 22(1):138-150. Disclosures No relevant conflicts of interest to declare.
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Coffey, Richard, et Mitchell D. Knutson. « The plasma membrane metal-ion transporter ZIP14 contributes to nontransferrin-bound iron uptake by human β-cells ». American Journal of Physiology-Cell Physiology 312, no 2 (1 février 2017) : C169—C175. http://dx.doi.org/10.1152/ajpcell.00116.2016.
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The relationship between iron and β-cell dysfunction has long been recognized as individuals with iron overload display an increased incidence of diabetes. This link is usually attributed to the accumulation of excess iron in β-cells leading to cellular damage and impaired function. Yet, the molecular mechanism(s) by which human β-cells take up iron has not been determined. In the present study, we assessed the contribution of the metal-ion transporters ZRT/IRT-like protein 14 and 8 (ZIP14 and ZIP8) and divalent metal-ion transporter-1 (DMT1) to iron uptake by human β-cells. Iron was provided to the cells as nontransferrin-bound iron (NTBI), which appears in the plasma during iron overload and is a major contributor to tissue iron loading. We found that overexpression of ZIP14 and ZIP8, but not DMT1, resulted in increased NTBI uptake by βlox5 cells, a human β-cell line. Conversely, siRNA-mediated knockdown of ZIP14, but not ZIP8, resulted in 50% lower NTBI uptake in βlox5 cells. In primary human islets, knockdown of ZIP14 also reduced NTBI uptake by 50%. Immunofluorescence analysis of islets from human pancreatic sections localized ZIP14 and DMT1 nearly exclusively to β-cells. Studies in primary human islets suggest that ZIP14 protein levels do not vary with iron status or treatment with IL-1β. Collectively, these observations identify ZIP14 as a major contributor to NTBI uptake by β-cells and suggest differential regulation of ZIP14 in primary human islets compared with other cell types such as hepatocytes.
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Hudek, Lee, L. C. Rai, David Freestone, Agnes Michalczyk, Maria Gibson, Y. F. Song et M. Leigh Ackland. « Bioinformatic and Expression Analyses of Genes Mediating Zinc Homeostasis in Nostoc punctiforme ». Applied and Environmental Microbiology 75, no 3 (14 novembre 2008) : 784–91. http://dx.doi.org/10.1128/aem.02481-08.
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ABSTRACT Zinc homeostasis was investigated in Nostoc punctiforme. Cell tolerance to Zn2+ over 14 days showed that ZnCl2 levels above 22 μM significantly reduced cell viability. After 3 days in 22 μM ZnCl2, ca. 12% of the Zn2+ was in an EDTA-resistant component, suggesting an intracellular localization. Zinquin fluorescence was detected within cells exposed to concentrations up to 37 μM relative to 0 μM treatment. Radiolabeled 65Zn showed Zn2+ uptake increased over a 3-day period, while efflux occurred more rapidly within a 3-h time period. Four putative genes involved in Zn2+ uptake and efflux in N. punctiforme were identified: (i) the predicted Co/Zn/Cd cation transporter, putative CDF; (ii) the predicted divalent heavy-metal cation transporter, putative Zip; (iii) the ATPase component and Fe/Zn uptake regulation protein, putative Fur; and (iv) an ABC-type Mn/Zn transport system, putative zinc ZnuC, ZnuABC system component. Quantitative real-time PCR indicated the responsiveness of all four genes to 22 μM ZnCl2 within 3 h, followed by a reduction to below basal levels after 24 h by putative ZIP, ZnuC, and Fur and a reduction to below basal level after 72 h by putative CDF efflux gene. These results demonstrate differential regulation of zinc transporters over time, indicating a role for them in zinc homeostasis in N. punctiforme.
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Zang, Zhong-Sheng, Yan-Ming Xu et Andy T. Y. Lau. « Molecular and pathophysiological aspects of metal ion uptake by the zinc transporter ZIP8 (SLC39A8) ». Toxicology Research 5, no 4 (2016) : 987–1002. http://dx.doi.org/10.1039/c5tx00424a.
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Dufner-Beattie, Jodi, Zhixin L. Huang, Jim Geiser, Wenhao Xu et Glen K. Andrews. « Generation and Characterization of Mice Lacking the Zinc Uptake Transporter ZIP3 ». Molecular and Cellular Biology 25, no 13 (1 juillet 2005) : 5607–15. http://dx.doi.org/10.1128/mcb.25.13.5607-5615.2005.
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ABSTRACT The mouse ZIP3 (SLC39A3) gene encodes an eight-transmembrane-domain protein that has been conserved in mammals and can function to transport zinc. To analyze the expression of ZIP3 in the early embryo and neonate and to determine its in vivo function, we generated ZIP3 null mice in which the ZIP3 open reading frame was replaced with that of the enhanced green fluorescent protein (EGFP) reporter. EGFP fluorescence revealed that ZIP3 was expressed in the inner cell mass of the blastocyst and later during embryonic development in many tissues. Elevated expression was apparent in the embryonic brain and neurotube and neonatal gonads. Homozygous knockout mice were viable and fertile and under normal growth conditions exhibited no obvious phenotypic abnormalities. Deletion of ZIP3 did not alter zinc homeostasis at the molecular level as assessed by essential metal levels and the expression of zinc-responsive genes. In knockout mice stressed with a zinc-deficient diet during pregnancy or at weaning, a subtle increase in the sensitivity to abnormal morphogenesis of the embryo and to depletion of thymic pre-T cells, respectively, was noted. These results suggest that this protein plays an ancillary role in zinc homeostasis in mice.
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Rampey, Rebekah A., Megan T. Baldridge, David C. Farrow, Sarah N. Bay et Bonnie Bartel. « Compensatory Mutations in Predicted Metal Transporters Modulate Auxin Conjugate Responsiveness in Arabidopsis ». G3 Genes|Genomes|Genetics 3, no 1 (1 janvier 2013) : 131–41. http://dx.doi.org/10.1534/g3.112.004655.
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Abstract Levels of the phytohormone indole-3-acetic acid (IAA) can be altered by the formation and hydrolysis of IAA conjugates. The isolation and characterization of Arabidopsis thaliana mutants with reduced IAA-conjugate sensitivity and wild-type IAA responses is advancing the understanding of auxin homeostasis by uncovering the factors needed for conjugate metabolism. For example, the discovery that the IAA-Ala-resistant mutant iar1 is defective in a protein in the ZIP family of metal transporters uncovered a link between metal homeostasis and IAA-conjugate sensitivity. To uncover additional factors impacting auxin conjugate metabolism, we conducted a genetic modifier screen and isolated extragenic mutations that restored IAA-amino acid conjugate sensitivity to the iar1 mutant. One of these suppressor mutants is defective in a putative cation diffusion facilitator, MTP5 (At3g12100; formerly known as MTPc2). Loss of MTP5 function restored IAA conjugate sensitivity to iar1 but not to mutants defective in IAA-amino acid conjugate amidohydrolases. Our results are consistent with a model in which MTP5 and IAR1 transport metals in an antagonistic fashion to regulate metal homeostasis within the subcellular compartment in which the IAA-conjugate amidohydrolases reside, and support previous suggestions that the ion composition in this compartment influences hydrolase activity.
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Napolitano, Jessica R., Ming-Jie Liu, Shengying Bao, Melissa Crawford, Patrick Nana-Sinkam, Estelle Cormet-Boyaka et Daren L. Knoell. « Cadmium-mediated toxicity of lung epithelia is enhanced through NF-κB-mediated transcriptional activation of the human zinc transporter ZIP8 ». American Journal of Physiology-Lung Cellular and Molecular Physiology 302, no 9 (1 mai 2012) : L909—L918. http://dx.doi.org/10.1152/ajplung.00351.2011.
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Cadmium (Cd), a toxic heavy metal and carcinogen that is abundantly present in cigarette smoke, is a cause of smoking-induced lung disease. SLC39A8 (ZIP8), a zinc transporter, is a major portal for Cd uptake into cells. We have recently identified that ZIP8 expression is under the transcriptional control of the NF-κB pathway. On the basis of this, we hypothesized that cigarette-smoke induced inflammation would increase ZIP8 expression in lung epithelia, thereby enhancing Cd uptake and cell toxicity. Herein we report that ZIP8 is a central mediator of Cd-mediated toxicity. TNF-α treatment of primary human lung epithelia and A549 cells induced ZIP8 expression, resulting in significantly higher cell death attributable to both apoptosis and necrosis following Cd exposure. Inhibition of the NF-κB pathway and ZIP8 expression significantly reduced cell toxicity. Zinc (Zn), a known cytoprotectant, prevented Cd-mediated cell toxicity via ZIP8 uptake. Consistent with cell culture findings, a significant increase in ZIP8 mRNA and protein expression was observed in the lung of chronic smokers compared with nonsmokers. From these studies, we conclude that ZIP8 expression is induced in lung epithelia in an NF-κB-dependent manner, thereby resulting in increased cell death in the presence of Cd. From this we contend that ZIP8 plays a critical role at the interface between micronutrient (Zn) metabolism and toxic metal exposure (Cd) in the lung microenvironment following cigarette smoke exposure. Furthermore, dietary Zn intake, or a lack thereof, may be a contributing factor in smoking-induced lung disease.
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Han, Tian-Long, Ting-Wei Tang, Pei-Hong Zhang, Min Liu, Jing Zhao, Jia-Shi Peng et Shuan Meng. « Cloning and Functional Characterization of SpZIP2 ». Genes 13, no 12 (17 décembre 2022) : 2395. http://dx.doi.org/10.3390/genes13122395.
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Zinc (Zn)-regulated and iron (Fe)-regulated transporter-like proteins (ZIP) are key players involved in the accumulation of cadmium (Cd) and Zn in plants. Sedum plumbizincicola X.H. Guo et S.B. Zhou ex L.H. Wu (S. plumbizincicola) is a Crassulaceae Cd/Zn hyperaccumulator found in China, but the role of ZIPs in S. plumbizincicola remains largely unexplored. Here, we identified 12 members of ZIP family genes by transcriptome analysis in S. plumbizincicola and cloned the SpZIP2 gene with functional analysis. The expression of SpZIP2 in roots was higher than that in the shoots, and Cd stress significantly decreased its expression in the roots but increased its expression in leaves. Protein sequence characteristics and structural analysis showed that the content of alanine and leucine residues in the SpZIP2 sequence was higher than other residues, and several serine, threonine and tyrosine sites can be phosphorylated. Transmembrane domain analysis showed that SpZIP2 has the classic eight transmembrane regions. The evolutionary analysis found that SpZIP2 is closely related to OsZIP2, followed by AtZIP11, OsZIP1 and AtZIP2. Sequence alignment showed that most of the conserved sequences among these members were located in the transmembrane regions. A further metal sensitivity assay using yeast mutant Δyap1 showed that the expression of SpZIP2 increased the sensitivity of the transformants to Cd but failed to change the resistance to Zn. The subsequent ion content determination showed that the expression of SpZIP2 increased the accumulation of Cd in yeast. Subcellular localization showed that SpZIP2 was localized to membrane systems, including the plasma membrane and endoplasmic reticulum. The above results indicate that ZIP member SpZIP2 participates in the uptake and accumulation of Cd into cells and might contribute to Cd hyperaccumulation in S. plumbizincicola.
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He, Lei, Kuppuswami Girijashanker, Timothy P. Dalton, Jodie Reed, Hong Li, Manoocher Soleimani et Daniel W. Nebert. « ZIP8, Member of the Solute-Carrier-39 (SLC39) Metal-Transporter Family : Characterization of Transporter Properties ». Molecular Pharmacology 70, no 1 (25 avril 2006) : 171–80. http://dx.doi.org/10.1124/mol.106.024521.
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Winslow, James W. W., Kirsten H. Limesand et Ningning Zhao. « The Functions of ZIP8, ZIP14, and ZnT10 in the Regulation of Systemic Manganese Homeostasis ». International Journal of Molecular Sciences 21, no 9 (7 mai 2020) : 3304. http://dx.doi.org/10.3390/ijms21093304.
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As an essential nutrient, manganese is required for the regulation of numerous cellular processes, including cell growth, neuronal health, immune cell function, and antioxidant defense. However, excess manganese in the body is toxic and produces symptoms of neurological and behavioral defects, clinically known as manganism. Therefore, manganese balance needs to be tightly controlled. In the past eight years, mutations of genes encoding metal transporters ZIP8 (SLC39A8), ZIP14 (SLC39A14), and ZnT10 (SLC30A10) have been identified to cause dysregulated manganese homeostasis in humans, highlighting the critical roles of these genes in manganese metabolism. This review focuses on the most recent advances in the understanding of physiological functions of these three identified manganese transporters and summarizes the molecular mechanisms underlying how the loss of functions in these genes leads to impaired manganese homeostasis and human diseases.
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Potocki, Slawomir, Daniela Valensin et Henryk Kozlowski. « The specificity of interaction of Zn2+, Ni2+ and Cu2+ ions with the histidine-rich domain of the TjZNT1 ZIP family transporter ». Dalton Trans. 43, no 26 (2014) : 10215–23. http://dx.doi.org/10.1039/c4dt00903g.
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The histidine-rich sequence from the loop between tansmembrane domains (TMDs) III and IV of ZIP transporters binds all studied metal ions with different geometries and with stability increasing in the series Ni2+ < Zn2+ ≪ Cu2+; a high specificity for Zn2+ is observed.
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Thompson, Khristy J., Jennifer Hein, Andrew Baez, Jose Carlo Sosa et Marianne Wessling-Resnick. « Manganese transport and toxicity in polarized WIF-B hepatocytes ». American Journal of Physiology-Gastrointestinal and Liver Physiology 315, no 3 (1 septembre 2018) : G351—G363. http://dx.doi.org/10.1152/ajpgi.00103.2018.
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Manganese (Mn) toxicity arises from nutritional problems, community and occupational exposures, and genetic risks. Mn blood levels are controlled by hepatobiliary clearance. The goals of this study were to determine the cellular distribution of Mn transporters in polarized hepatocytes, to establish an in vitro assay for hepatocyte Mn efflux, and to examine possible roles the Mn transporters would play in metal import and export. For these experiments, hepatocytoma WIF-B cells were grown for 12–14 days to achieve maximal polarity. Immunoblots showed that Mn transporters ZIP8, ZnT10, ferroportin (Fpn), and ZIP14 were present. Indirect immunofluorescence microscopy localized Fpn and ZIP14 to WIF-B cell basolateral domains whereas ZnT10 and ZIP8 associated with intracellular vesicular compartments. ZIP8-positive structures were distributed uniformly throughout the cytoplasm, but ZnT10-positive vesicles were adjacent to apical bile compartments. WIF-B cells were sensitive to Mn toxicity, showing decreased viability after 16 h exposure to >250 μM MnCl2. However, the hepatocytes were resistant to 4-h exposures of up to 500 μM MnCl2 despite 50-fold increased Mn content. Washout experiments showed time-dependent efflux with 80% Mn released after a 4 h chase period. Hepcidin reduced levels of Fpn in WIF-B cells, clearing Fpn from the cell surface, but Mn efflux was unaffected. The secretory inhibitor, brefeldin A, did block release of Mn from WIF-B cells, suggesting vesicle fusion may be involved in export. These results point to a possible role of ZnT10 to import Mn into vesicles that subsequently fuse with the apical membrane and empty their contents into bile. NEW & NOTEWORTHY Polarized WIF-B hepatocytes express manganese (Mn) transporters ZIP8, ZnT10, ferroportin (Fpn), and ZIP14. Fpn and ZIP14 localize to basolateral domains. ZnT10-positive vesicles were adjacent to apical bile compartments, and ZIP8-positive vesicles were distributed uniformly throughout the cytoplasm. WIF-B hepatocyte Mn export was resistant to hepcidin but inhibited by brefeldin A, pointing to an efflux mechanism involving ZnT10-mediated uptake of Mn into vesicles that subsequently fuse with and empty their contents across the apical bile canalicular membrane.
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Liu, Liu, Xiangrong Geng, Yihong Cai, Bryan Copple, Masafumi Yoshinaga, Jian Shen, Daniel W. Nebert, Hua Wang et Zijuan Liu. « Hepatic ZIP8 deficiency is associated with disrupted selenium homeostasis, liver pathology, and tumor formation ». American Journal of Physiology-Gastrointestinal and Liver Physiology 315, no 4 (1 octobre 2018) : G569—G579. http://dx.doi.org/10.1152/ajpgi.00165.2018.
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Zrt/Irt-like protein 8 (ZIP8) (encoded by Slc39a8) is a multifunctional membrane transporter that influxes essential metal cations Zn2+, Mn2+, Fe2+, and nonmetal inorganic selenite (HSeO3−). Physiological roles of ZIP8 in different cell types and tissues remain to be elucidated. We aimed to investigate ZIP8 functions in liver. Two mouse models were used in this study: 1) 13- to 21-mo-old Slc39a8(+/neo) hypomorphs having diminished ZIP8 levels and 2) a liver-specific ZIP8 acute knockdown mouse (Ad-shZip8). Histology, immunohistochemistry, and Western blotting were used to investigate ZIP8-deficiency effects on hepatic injury, inflammatory changes, and oxidative stress. Selenium (Se) and zinc (Zn) were quantified in tissues by inductively coupled plasma-mass spectrophotometry. We found that ZIP8 is required to maintain normal liver function; moderate or acute decreases in ZIP8 activity resulted in hepatic pathology. Spontaneous liver neoplastic nodules appeared in ~50% of Slc39a8(+/neo) between 13 and 21 mo of age, exhibiting features of inflammation, fibrosis, and liver injury. In Ad-shZip8 mice, significant hepatomegaly was observed; histology showed ZIP8 deficiency was associated with hepatocyte injury, inflammation, and proliferation. Significant decreases in Se, but not Zn, were found in Ad-shZip8 liver. Consistent with this Se deficit, liver expression of selenoproteins glutathione peroxidases 1 and 2 was downregulated, along with decreases in antioxidant superoxide dismutases 1 and 2, consistent with increased oxidative stress. Thus, ZIP8 plays an important role in maintaining normal hepatic function, likely through regulating Se homeostasis and redox balance. Hepatic ZIP8 deficiency is associated with liver pathology, including oxidative stress, inflammation, proliferation, and hepatocellular injury. NEW & NOTEWORTHY Zrt/Irt-like protein 8 (ZIP8) is a multifunctional membrane transporter that facilitates biometal and mineral uptake. The role of ZIP8 in liver physiology has not been previously investigated. Liu et al. discovered unique ZIP8 functions, i.e., regulation of hepatic selenium content and association of ZIP8 deficiency in mouse liver with liver defects.
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Hu, Jian. « Structural Biochemistry of the Zrt-/Irt-like Protein (ZIP) Transition Metal Transporters ». Biophysical Journal 120, no 3 (février 2021) : 73a. http://dx.doi.org/10.1016/j.bpj.2020.11.660.
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Leyn, Semen A., et Dmitry A. Rodionov. « Comparative Genomics of DtxR Family Regulons for Metal Homeostasis in Archaea ». Journal of Bacteriology 197, no 3 (17 novembre 2014) : 451–58. http://dx.doi.org/10.1128/jb.02386-14.
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The DtxR family consists of metal-dependent transcription factors (DtxR-TFs) that regulate the expression of genes involved in metal homeostasis in the cell. The majority of characterized DtxR-TFs belong toBacteria. In the current work, we applied a comparative genomics approach to predict DNA-binding sites and reconstruct regulons for DtxR-TFs inArchaea. As a result, we inferred 575 candidate binding sites for 139 DtxR-TFs in 77 genomes from 15 taxonomic orders. Novel DNA motifs of archaeal DtxR-TFs that have a common palindromic structure were classified into 10 distinct groups. By combining functional regulon reconstructions with phylogenetic analysis, we selected 28 DtxR-TF clades and assigned them metal specificities and regulator names. The reconstructed FetR (ferrous iron), MntR (manganese), and ZntR (zinc) regulons largely contain known or putative metal uptake transporters from the FeoAB, NRAMP, ZIP, and TroA families. A novel family of putative iron transporters (named Irt), including multiple FetR-regulated paralogs, was identified in iron-oxidizingArchaeafrom theSulfolobalesorder. The reconstructed DtxR-TF regulons were reconciled with available transcriptomics data inArchaeoglobus,Halobacterium, andThermococcusspp.
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Notova, Svetlana V., Tatyana V. Kazakova, Olga V. Marshinskaya et Oksana V. Shoshina. « Metal-ligand forms of iron and zinc in the human body ». Kazan medical journal 103, no 2 (12 avril 2022) : 259–68. http://dx.doi.org/10.17816/kmj2022-259.
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Metals have a wide range of effects on biological processes, playing an important role in maintaining the functioning of the human body. However, many metals, including essential elements, can have a toxic effect on the body, leading to pathological processes. The biological role of an element depends on a number of physicochemical facts, such as the oxidation degree and the formation of metal-ligand organic and inorganic complexes. For example, most of the iron binds to transferrin and ferritin ensuring the safe transportation of the fenton-active trivalent metal ions in the bloodstream. Free Fe3+ ions lead to the formation of reactive oxygen species and further damage of cell structures. Thus, the chemical form of the element determines the toxicokinetics and toxicodynamics of metals. Knowledge in total exposure of elements in biological fluids is not enough to understand the complex mechanism of biological and abnormal reactions. It is necessary to study the interaction of metal elements with various ligands such as high- and low-molecular compounds (proteins, polysaccharides, nucleic acids, citrates, amino acids). In this regard, the application of modern analytical methods is becoming increasingly important to obtain qualitative and quantitative data on elements, ionic forms, speciation and functions in biological systems. The combination of these methods is called speciation analysis, which is a well-established way to study the biological role and metabolism of trace elements. This article reviews the main metal-ligand forms of iron (transferrin, albumin, ferritin and citrate) and zinc (albumin, 2-macroglobulin, IgG, transcuprein, metallothioneins, ZIP and ZnT transporters). This information can be useful both in fundamental and applied researches in the biology and medicine.
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Lin, Wen, David R. Vann, Paschalis-Thomas Doulias, Tao Wang, Gavin Landesberg, Xueli Li, Emanuela Ricciotti et al. « Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity ». Journal of Clinical Investigation 127, no 6 (8 mai 2017) : 2407–17. http://dx.doi.org/10.1172/jci90896.
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Girijashanker, Kuppuswami, Lei He, Manoocher Soleimani, Jodie M. Reed, Hong Li, Zhiwei Liu, Bin Wang, Timothy P. Dalton et Daniel W. Nebert. « Slc39a14 Gene Encodes ZIP14, A Metal/Bicarbonate Symporter : Similarities to the ZIP8 Transporter ». Molecular Pharmacology 73, no 5 (12 février 2008) : 1413–23. http://dx.doi.org/10.1124/mol.107.043588.
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Adulcikas, John, Sabrina Sonda, Shaghayegh Norouzi, Sukhwinder Sohal et Stephen Myers. « Targeting the Zinc Transporter ZIP7 in the Treatment of Insulin Resistance and Type 2 Diabetes ». Nutrients 11, no 2 (15 février 2019) : 408. http://dx.doi.org/10.3390/nu11020408.
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Type 2 diabetes mellitus (T2DM) is a disease associated with dysfunctional metabolic processes that lead to abnormally high levels of blood glucose. Preceding the development of T2DM is insulin resistance (IR), a disorder associated with suppressed or delayed responses to insulin. The effects of this response are predominately mediated through aberrant cell signalling processes and compromised glucose uptake into peripheral tissue including adipose, liver and skeletal muscle. Moreover, a major factor considered to be the cause of IR is endoplasmic reticulum (ER) stress. This subcellular organelle plays a pivotal role in protein folding and processes that increase ER stress, leads to maladaptive responses that result in cell death. Recently, zinc and the proteins that transport this metal ion have been implicated in the ER stress response. Specifically, the ER-specific zinc transporter ZIP7, coined the “gate-keeper” of zinc release from the ER into the cytosol, was shown to be essential for maintaining ER homeostasis in intestinal epithelium and myeloid leukaemia cells. Moreover, ZIP7 controls essential cell signalling pathways similar to insulin and activates glucose uptake in skeletal muscle. Accordingly, ZIP7 may be essential for the control of ER localized zinc and mechanisms that disrupt this process may lead to ER-stress and contribute to IR. Accordingly, understanding the mechanisms of ZIP7 action in the context of IR may provide opportunities to develop novel therapeutic options to target this transporter in the treatment of IR and subsequent T2DM.
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Ziliotto, Silvia, Julia M. W. Gee, Ian O. Ellis, Andrew R. Green, Pauline Finlay, Anna Gobbato et Kathryn M. Taylor. « Activated zinc transporter ZIP7 as an indicator of anti-hormone resistance in breast cancer ». Metallomics 11, no 9 (2019) : 1579–92. http://dx.doi.org/10.1039/c9mt00136k.
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Hermann, Evan, Emily Chambers, Danielle Davis, Mckale Montgomery et Winyoo Chowanadisai. « Brain MRI Phenotypes Associated with Polymorphisms at or Near the SLC39A8 (ZIP8) Metal Transporter Gene ». Current Developments in Nutrition 4, Supplement_2 (29 mai 2020) : 1808. http://dx.doi.org/10.1093/cdn/nzaa067_035.
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Abstract Objectives The SLC39A8 gene encodes a divalent metal transporter, ZIP8. ZIP8 polymorphisms are associated with pleiotropic effects including altered risks for schizophrenia. Our objective is to determine the different brain MRI phenotypes associated at or near the SLC39A8 (ZIP8) genetic locus using a phenome-wide association (PheWAS) approach followed by joint and conditional association analysis. Methods Using the summary statistics database containing brain MRI genome-wide association study (GWAS) data, we systematically selected all brain MRI phenotypes which were associated with single-nucleotide polymorphisms (SNPs) within 1 million bp of the SLC39A8 genetic locus, as defined as reaching a P-value significance cutoff of P < 5.0 × 10–8. For all brain MRI phenotypes reaching significance, we used GCTA-COJO to determine the number of independent association signals using settings of P < 1.0 × 10–5 and a window of 10 million base pairs. Using SNPclip and the European 1000 Genomes linkage panel with a linkage disequilibrium cutoff of r2 > 0.8, we identified SNP candidates at each index SNP. Linkage equilibrium for brain phenotypes with multiple independent signals was confirmed by LDpair. Results We identified 25 brain MRI phenotypes that vary due to MRI type and brain region that all contain a SNP associated with the SLC39A8 locus. All of these datasets have at least 1 index SNP directly labeling or in high linkage disequilibrium with rs13107325, which encodes a missense mutation in the SLC39A8 (ZIP8). Among the 25 datasets, an additional 4 association signals were identified by GCTA-COJO and confirmed to be in linkage equilibrium with rs13107325 using LDpair. For these additional association signals, probable causative SNPs were identified from the index SNP using SNPclip. Conclusions From the 25 brain MRI phenotypes, we identified new probable causative SNPs in addition to a previously reported missense SNP (rs13107325) associated with schizophrenia. This study provides leads into how SNPs in genes involved in trace metal transport influence brain structures and affect risks for schizophrenia. Funding Sources This work was funded by grants from the Oklahoma Center for the Advancement of Science and Technology and the Oklahoma Agricultural Experiment Station.
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Schmitt-Ulms, Gerold, Sepehr Ehsani, Joel C. Watts, David Westaway et Holger Wille. « Evolutionary Descent of Prion Genes from the ZIP Family of Metal Ion Transporters ». PLoS ONE 4, no 9 (28 septembre 2009) : e7208. http://dx.doi.org/10.1371/journal.pone.0007208.
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Wan, Huixue, Jiayi Du, Jiali He, Deguo Lyu et Huifeng Li. « Copper accumulation, subcellular partitioning and physiological and molecular responses in relation to different copper tolerance in apple rootstocks ». Tree Physiology 39, no 7 (17 mai 2019) : 1215–34. http://dx.doi.org/10.1093/treephys/tpz042.
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Abstract To unravel the physiological and molecular regulation mechanisms underlying the variation in copper (Cu)accumulation, translocation and tolerance among five apple rootstocks, seedlings were exposed to either basal or excess Cu. Excess Cu suppressed plant biomass and root architecture, which was less pronounced in Malus prunifolia Borkh., indicating its relatively higher Cu tolerance. Among the five apple rootstocks, M. prunifolia exhibited the highest Cu concentration and bio-concentration factor in roots but the lowest translocation factor, indicating its greater ability to immobilize Cu and restrict translocation to the aerial parts. Higher Cu concentration in cell wall fraction but lower Cu proportion in membrane-containing and organelle-rich fractions were found in M. prunifolia. Compared with the other four apple rootstocks under excess Cu conditions, M. prunifolia had a lower increment of hydrogen peroxide in roots and leaves and malondialdehyde in roots, but higher concentrations of carbohydrates and enhanced antioxidants. Transcript levels of genes involved in Cu uptake, transport and detoxification revealed species-specific differences that are probably related to alterations in Cu tolerance. M. prunifolia had relatively higher gene transcript levels including copper transporters 2 (COPT2), COPT6 and zinc/iron-regulated transporter-related protein 2 (ZIP2), which probably took part in Cu uptake, and C-type ATP-binding cassette transporter 2 (ABCC2), copper chaperone for Cu/Zn superoxide dismutase (CCS), Cu/Zn superoxide dismutase 1 (CSD1) and metallothionein 2 (MT2) probably implicated in Cu detoxification, and relatively lower mRNA levels of yellow stripe-like transporter 3 (YSL3) and heavy metal ATPase 5 (HMA5) involved in transport of Cu to aerial parts. These results suggest that M. prunifolia is more tolerant to excess Cu than the other four apple rootstocks under the current experimental conditions, which is probably attributed to more Cu retention in roots, subcellular partitioning, well-coordinated antioxidant defense mechanisms and transcriptional expression of genes involved in Cu uptake, translocation and detoxification.
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Ito, Keisuke, Tomoya Fujie, Masahiro Shimomura, Tsuyoshi Nakano, Chika Yamamoto et Toshiyuki Kaji. « TGF-β1 Potentiates the Cytotoxicity of Cadmium by Induction of a Metal Transporter, ZIP8, Mediated by the ALK5-Smad2/3 and ALK5-Smad3-p38 MAPK Signal Pathways in Cultured Vascular Endothelial Cells ». International Journal of Molecular Sciences 23, no 1 (31 décembre 2021) : 448. http://dx.doi.org/10.3390/ijms23010448.
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Vascular endothelial cells cover the luminal surface of blood vessels in a monolayer and play a role in the regulation of vascular functions, such as the blood coagulation-fibrinolytic system. When the monolayer is severely or repeatedly injured, platelets aggregate at the damaged site and release transforming growth factor (TGF)-β1 in large quantities from their α-granules. Cadmium is a heavy metal that is toxic to various organs, including the kidneys, bones, liver, and blood vessels. Our previous study showed that the expression level of Zrt/Irt-related protein 8 (ZIP8), a metal transporter that transports cadmium from the extracellular fluid into the cytosol, is a crucial factor in determining the sensitivity of vascular endothelial cells to cadmium cytotoxicity. In the present study, TGF-β1 was discovered to potentiate cadmium-induced cytotoxicity by increasing the intracellular accumulation of cadmium in cells. Additionally, TGF-β1 induced the expression of ZIP8 via the activin receptor-like kinase 5-Smad2/3 signaling pathways; Smad3-mediated induction of ZIP8 was associated with or without p38 mitogen-activated protein kinase (MAPK). These results suggest that the cytotoxicity of cadmium to vascular endothelial cells increases when damaged endothelial monolayers that are highly exposed to TGF-β1 are repaired.
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Kelleher, Shannon L., Veronica Lopez, Bo Lönnerdal, Jodi Dufner-Beattie et Glen K. Andrews. « Zip3 (Slc39a3) functions in zinc reuptake from the alveolar lumen in lactating mammary gland ». American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 297, no 1 (juillet 2009) : R194—R201. http://dx.doi.org/10.1152/ajpregu.00162.2009.
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The lactating mammary gland is composed of multiple cell types that tightly coordinate the accumulation, production, and secretion of milk components, including essential metals such as zinc (Zn). Our previous studies in animal and cell models implicated the Zn transporter Zip3 (Slc39a3) in mammary gland Zn acquisition. Herein, we investigated this hypothesis directly by utilizing Zip3-null mice. Our data verify that Zip3 is expressed in secretory mammary cells; however, Zip3 does not play a major role in Zn import from the maternal circulation. Importantly, the primary localization of Zip3 was associated with the luminal membrane of the secretory mammary cells. Consistent with this localization, Zn transfer studies using 65Zn revealed that Zn retention in the secreted milk pool and milk Zn concentration was higher in Zip3-null compared with wild-type mice. Although total mammary gland Zn concentration was not altered, Zip3-null mice also had altered mammary tissue architecture, increased number of apoptotic cells, and reduced mammary gland weight implicating subtle changes in Zip3-mediated intracellular Zn pools in apoptosis regulation. Taken together, our data indicate that Zip3 does not participate in the acquisition of Zn from maternal circulation for secretion into milk but, in contrast, primarily plays a role in the reuptake and cellular retention of Zn in the mammary gland from the previously secreted milk pool, thus regulating cellular function.
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Wu, Jian, Fang-Jie Zhao, Artak Ghandilyan, Barbara Logoteta, Myriam Olortegui Guzman, Henk Schat, Xiaowu Wang et Mark G. M. Aarts. « Identification and functional analysis of two ZIP metal transporters of the hyperaccumulator Thlaspi caerulescens ». Plant and Soil 325, no 1-2 (16 septembre 2009) : 79–95. http://dx.doi.org/10.1007/s11104-009-0151-6.
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Kosman, Daniel J. « A holistic view of mammalian (vertebrate) cellular iron uptake ». Metallomics 12, no 9 (2020) : 1323–34. http://dx.doi.org/10.1039/d0mt00065e.
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Reymond, Jean-Louis. « Molecular Similarity for Drug Discovery, Target Prediction and Chemical Space Visualization ». CHIMIA 76, no 12 (21 décembre 2022) : 1045. http://dx.doi.org/10.2533/chimia.2022.1045.
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Similar drug molecules often have similar properties and activities. Therefore, quantifying molecular similarity is central to drug discovery and optimization. Here I review computational methods using molecular similarity measures developed in my group within the interdisciplinary network NCCR TransCure investigating the physiology, structural biology and pharmacology of ion channels and membrane transporters. We designed a 3D molecular shape and pharmacophore comparison algorithm to optimize weak and unselective inhibitors by scaffold hopping and discovered potent and selective inhibitors of the ion channels TRPV6 and TRPM4, of endocannabinoid membrane transport, and of the divalent metal transporters DMT1 and ZIP8. We predicted off-target effects by combining molecular similarity searches from different molecular fingerprints against target annotated compounds from the ChEMBL database. Finally, we created interactive chemical space maps reflecting molecular similarities to facilitate the selection of screening compounds and the analysis of screening results. These different tools are available online at https://gdb.unibe.ch/tools/.
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Hudek, L., L. A. Pearson, A. Michalczyk, B. A. Neilan et M. L. Ackland. « Functional characterization of the twin ZIP/SLC39 metal transporters, NpunF3111 and NpunF2202 in Nostoc punctiforme ». Applied Microbiology and Biotechnology 97, no 19 (30 juin 2013) : 8649–62. http://dx.doi.org/10.1007/s00253-013-5047-y.
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