ZIP Family Research Articles

ZnT8 Haploinsufficiency Impacts MIN6 Cell Zinc Content and β-Cell Phenotype via ZIP-ZnT8 Coregulation.

The zinc transporter ZnT8 (SLC30A8) localises to insulin secretory granules of β-cells where it facilitates zinc uptake for insulin crystallisation. ZnT8 abundance has been linked to β-cell survival and functional phenotype. However, the consequences of ZnT8 haploinsufficiency for β-cell zinc trafficking and function remain unclear. Since investigations in human populations have shown SLC30A8 truncating polymorphisms to decrease the risk of developing Type 2 Diabetes, we hypothesised that ZnT8 haploinsufficiency would improve β-cell function and maintain the endocrine phenotype. We used CRISPR/Cas9 technology to generate ZnT8 haploinsufficient mouse MIN6 β-cells and showed that ZnT8 haploinsufficiency is associated with downregulation of mRNAs for Slc39a8 and Slc39a14, which encode for the zinc importers, Znt- and Irt-related proteins 8 (ZIP8) and 14 (ZIP14), and with lowered total cellular zinc content. ZnT8 haploinsufficiency disrupts expression of a distinct array of important β-cell markers, decreases cellular proliferation via mitogen-activated protein (MAP) kinase cascades and downregulates insulin gene expression. Thus, ZnT8 cooperates with zinc importers of the ZIP family to maintain β-cell zinc homeostasis. In contrast to the hypothesis, lowered ZnT8 expression reduces MIN6 cell survival by affecting zinc-dependent transcription factors that control the β-cell phenotype.

Activated zinc transporter ZIP7 as an indicator of anti-hormone resistance in breast cancer.

ZIP7, a member of the ZIP family of zinc importers, resides on the endoplasmic reticulum membrane and transports zinc from intracellular stores to the cytoplasm after activation by CK2 phosphorylation on two serine residues (S275 and S276). ZIP7 is known to be required for the growth of anti-hormone resistant breast cancer models, especially those with acquired tamoxifen resistance developed from MCF-7. Using our new pS275S276ZIP7 antibody which only recognises activated ZIP7 (pZIP7), we have demonstrated that the hyperactivation of ZIP7 is prevalent in tamoxifen-resistant breast cancer cells. This evidence suggests that pZIP7 might have potential as a biomarker of acquired resistance to such anti-hormones in breast cancer, a current unmet clinical need. In this regard, we have also developed a new immunohistochemical assay for pZIP7 which allowed pZIP7 to be tested on a small clinical series of breast cancer tissues confirming its prevalence in such tumours and relationship to a variety of clinicopathological parameters and biomarkers previously associated with endocrine resistant phenotypes, notably increased activated MAPK signalling, expression of ErbB2, CD71 and the proto-oncogene c-Fos, as well as with increased tumour grade.

Novel mechanism of endocrine disruption by fungicides through binding to the membrane androgen receptor, ZIP9 (SLC39A9), and antagonizing rapid testosterone induction of the intrinsic apoptotic pathway

A variety of pesticides including vinclozolin, its metabolite M2 (3′,5′-dichloro-2-hydroxy-2-methylbut-3-enanilide), and prochloraz have been shown to exert antiandrogenic effects in animal models by competing with androgen binding to nuclear androgen receptors (nAR) and decreasing transcription of androgen-responsive genes. However, it is not known whether these pesticide antiandrogens also interfere with rapid (often described as nongenomic, nonclassical) androgen actions mediated by membrane androgen receptors (mARs). We recently discovered that ZIP9, a member of the zinc transporter ZIP (SLC39A) family, is a specific, high-affinity mAR that mediates rapid testosterone-dependent signaling, zinc influx, and apoptosis in breast and prostate cancer cell lines. Possible disruption by prochloraz, vinclozolin, and M2 of androgen actions through this mAR was investigated in vitro in PC-3 prostate cancer cells (nAR-) over expressing human ZIP9 (PC3-ZIP9 cells). Single-point competitive binding assays showed 1 μM and 10 μM concentrations of all three pesticides displaced specific [3H]-testosterone binding to PC3-ZIP9 cell membranes with binding affinities <10% that of testosterone. The pesticides also exerted antiandrogen actions through ZIP9. Co-treatments with 100 nM prochloraz, vinclozolin and M2 blocked or attenuated the 20 nM testosterone-induced increases in apoptosis, intracellular free zinc levels, and expression of the proapoptotic gene, Bax. Prochloraz also attenuated testosterone activation of MAPkinase. The finding that prochloraz, vinclozolin and M2 are effective competitors of [3H]-testosterone binding to ZIP9 and block testosterone actions mediated through ZIP9 in vitro at nanomolar concentrations suggests that androgen functions mediated by ZIP9 are also susceptible to disruption by pesticide antiandrogens with potential adverse effects on human health.

Manganese influx and expression of ZIP8 is essential in primary myoblasts and contributes to activation of SOD2.

Trace elements such as copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn) function as enzyme cofactors and second messengers in cell signaling. Trace elements are emerging as key regulators of differentiation and development of mammalian tissues including blood, brain, and skeletal muscle. We previously reported an influx of Cu and dynamic expression of metal transporters during differentiation of skeletal muscle cells. Here, we demonstrate that during differentiation of skeletal myoblasts an increase of Mn, Fe and Zn also occurs. Interestingly the Mn increase is concomitant with increased Mn-dependent SOD2 levels. To better understand the Mn import pathway in skeletal muscle cells, we probed the functional relevance of the closely related proteins ZIP8 and ZIP14, which are implicated in Zn, Mn, and Fe transport. Partial depletion of ZIP8 severely impaired growth of myoblasts and led to cell death under differentiation conditions, indicating that ZIP8-mediated metal transport is essential in skeletal muscle cells. Moreover, knockdown of Zip8 impaired activity of the Mn-dependent SOD2. Growth defects were partially rescued only by Mn supplementation to the medium, suggesting additional functions for ZIP8 in the skeletal muscle lineage. Restoring wild type Zip8 into the knockdown cells rescued the proliferation and differentiation phenotypes. On the other hand, knockdown of Zip14, had only a mild effect on myotube size, consistent with a role for ZIP14 in muscle hypertrophy. Simultaneous knockdown of both Zip8 and Zip14 further impaired differentiation and led cell death. This is the first report on the functional relevance of two members of the ZIP family of metal transporters in the skeletal muscle lineage, and further supports the paradigm that trace metal transporters are important modulators of mammalian tissue development.

Membrane Androgen Receptors Unrelated to Nuclear Steroid Receptors.

Rapid (nongenomic) membrane-initiated androgen actions have been described in nuclear androgen receptor-null cells. Four distinct proteins have been proposed as membrane androgen receptors (mARs) or sensors. Transient receptor potential melastatin 8 (TRPM8) is a calcium channel that acts as a pain receptor and mediates androgen- and menthol-induced increases in calcium levels and survival of prostate cancer cells. Testosterone (T) directly interacts with TRPM8, but extensive androgen receptor binding studies to confirm its role as an mAR are lacking. Oxoeicosanoid receptor 1 (OXER1) is highly expressed in prostate cancer tissues, and its major ligand, 5-oxoeicosatretraenoic acid (5-oxo-ETE), is a potent inducer of prostate cancer cell proliferation and survival. T competes for 5-oxo-ETE binding to OXER1 and antagonizes 5-oxo-ETE-mediated inhibition of cAMP production. However, OXER1 does not meet a traditional criterion for its designation as an mAR because T treatment alone does not alter cAMP signaling. GPRC6A is a class C G protein-coupled receptor activated by l-α-amino acids and is modulated by calcium. Although there has been controversy over the proposed role of T as a GPRC6A ligand, androgen induction of GPRC6A signaling has recently been confirmed by several researchers. ZIP9 belongs to the zinc transporter ZIP (SLC39A) family and displays specific T binding characteristic of an mAR. ZIP9 mediates androgen-dependent intracellular signaling and apoptosis of breast and prostate cancer cells through activation of G proteins. Androgen-signaling functions of ZIP9 have been confirmed in other cells, but the overall importance of ZIP9 in androgen physiology remains unclear. Here, the current status of these four proteins as mARs or sensors is critically reviewed.

An extracellular histidine-containing motif in the zinc transporter ZIP4 plays a role in zinc sensing and zinc-induced endocytosis in mammalian cells

Zinc is an essential trace element that serves as a cofactor for enzymes in critical biochemical processes and also plays a structural role in numerous proteins. Zinc transporter ZIP4 (ZIP4) is a zinc importer required for dietary zinc uptake in the intestine and other cell types. Studies in cultured cells have reported that zinc stimulates the endocytosis of plasma membrane-localized ZIP4 protein, resulting in reduced cellular zinc uptake. Thus, zinc-regulated trafficking of ZIP4 is a key means for regulating cellular zinc homeostasis, but the underlying mechanisms are not well understood. In this study, we used mutational analysis, immunoblotting, HEK293 cells, and immunofluorescence microscopy to identify a histidine-containing motif (398HTH) in the first extracellular loop that is required for high sensitivity to low zinc concentrations in a zinc-induced endocytic response of mouse ZIP4 (mZIP4). Moreover, using synthetic peptides with selective substitutions and truncated mZIP4 variants, we provide evidence that histidine residues in this motif coordinate a zinc ion in mZIP4 homodimers at the plasma membrane. These findings suggest that 398HTH is an important zinc-sensing motif for eliciting high-affinity zinc-stimulated endocytosis of mZIP4 and provide insight into cellular mechanisms for regulating cellular zinc homeostasis in mammalian cells.

The presence and response to Zn of ZnT family mRNAs in human dental pulp.

Zinc (Zn) is distributed throughout the body and within cells by saturable processes mediated by the transport proteins of the ZnT (SLC30) and ZIP (SLC39) families. The two families function in opposite directions. ZnT transporters mediate cellular zinc efflux or intracellular sequestration. Zn is found in human tooth enamel and dentine at levels that have been related to environmental exposures, such as pollution, disease, and dietary intake. The mechanism by which Zn in the odontoblast is deposited in the hard tissue of the tooth, however, is unknown but is important in determining the physical properties, and hence resilience, of enamel and in the context of the use of tooth zinc level as a biomarker of exposure. We hypothesised that zinc efflux mediated by members of the ZnT family of 10 transporters is a key step in this process and is regulated by zinc availability through effects on mRNA levels. Thus, we determined the profile of ZnT transporter mRNA in a human active-secretory odontoblast-like cell model under conditions of high- and low-extracellular Zn concentration and determined if the same transporter mRNAs were present in human dental pulp. ZnT1, ZnT5 and ZnT9 mRNAs were detected by RT-PCR in both the secretory odontoblast cells and human dental pulp. ZnT2, ZnT3 and ZnT10 mRNAs were not detected, and ZnT4 mRNA was detected in secretory odontoblasts only, which may be indicative of a specialised zinc efflux function during the active secretory phase of tooth development. ZnT1 mRNA was significantly increased in response to extracellular Zn exposure (60 μM) after 24 h. The presence of Zn transporter mRNAs in secretory odontoblasts and dental pulp indicates that the corresponding transport proteins function to deposit zinc in the dental hard tissues. The responsiveness of ZnT1 in odontoblasts to zinc availability is concordant with this being a process that is regulated to maintain cellular Zn homeostasis and that is a mediator of the relationship between environmental Zn exposure and dental Zn deposition. These findings have likely relevance to human dental health through effects of Zn transporter expression level on the hard tissue properties.

Functional Analysis of NtZIP4B and Zn Status-Dependent Expression Pattern of Tobacco ZIP Genes.

Tobacco is frequently considered as a plant useful for phytoremediation of metal-contaminated soil, despite the mechanisms for regulation of uptake and accumulation being largely unknown. Here we cloned and characterized a new tobacco Zn and Cd transporter NtZIP4B from the ZIP family (ZRT-IRT-Like proteins). It complemented the Zn-uptake defective yeast mutant zrt1zrt2, and rendered the wild type DY1457 yeast more sensitive to Cd. Bioinformatic analysis and transient expression of the NtZIP4B-GFP fusion protein in tobacco leaves indicated its localization to the plasma membrane. Real-time q-PCR based analysis showed that it is expressed in all vegetative organs with the highest level in leaves. The Zn status determined transcript abundance; NtZIP4B was upregulated by Zn-deficiency and downregulated by Zn excess. At the tissue level, in roots NtZIP4B is expressed in the vasculature of the middle part of the roots and in surrounding tissues including the root epidermis; in leaves primarily in the vasculature. Bioinformatic analysis identified two copies of ZIP4 in tobacco, NtZIP4A and NtZIP4B with 97.57% homology at the amino acid level, with the same expression pattern for both, indicating a high degree of functional redundancy. Moreover, the present study provides new insights into the coordinated function of NtZIP1, NtZIP2, NtZIP4, NtZIP5, NtZIP8, NtIRT1, and NtIRT1-like in response to low-to-high Zn status. Leaves were the major site of NtZIP4, NtZIP5, and NtZIP8 expression, and roots for NtZIP1, NtZIP2, NtIRT1, and NtIRT1-like. Contrasting expression level in the apical and basal root parts indicates distinct roles in root-specific processes likely contributing to the regulation of Zn root-to-shoot translocation. In summary, new insight into the role of ZIP genes in Zn homeostasis pointing to their overlapping and complementary functions, offers opportunities for strategies to modify Zn and Cd root/shoot partition in tobacco.

Zinc uptake in the Basidiomycota: Characterization of zinc transporters in Ustilago maydis.

At present, the planet faces a change in the composition and bioavailability of nutrients. Zinc deficiency is a widespread problem throughout the world. It is imperative to understand the mechanisms that organisms use to adapt to the deficiency of this micronutrient. In the Ascomycetes fungi, the ZIP family of proteins is one of the most important for zinc transport and includes high affinity Zrt1p and low zinc affinity Zrt2p transporters. After identification and characterization of ZRT1/ZRT2-like genes in Ustilago maydis we conclude that they encode for high and low zinc affinity transporters, with no apparent iron transport activity. These conclusions were supported by the gene deletion in Ustilago and the functional characterization of ZRT1/ZRT2-like genes by measuring the intracellular zinc content over a range of zinc availability. The functional complementation of the S. cerevisiae ZRT1Δ ZRT2Δ mutant with U. maydis genes supports this as well. U. maydis ZRT2 gene, was found to be regulated by pH through Rim101 pathway, thus providing novel insights into how this Basidiomycota fungus can adapt to different levels of Zn availability.

Effect of the Simultaneous Action of Zinc and Chromium on Arthrobacter spp.

Bacteria are regarded as the most effective in the detoxification of heavy metals, being environmental compatible. Metalloresistant bacteria are usually found in nature in highly contaminated environment where they interact with a combination of several toxic metals. For the present research, Arthrobacter oxydans and Arthrobacter globiformis have been isolated from the soil samples of the most polluted regions of Georgia, rich with manganese and iron, and contain co-produced toxic metals such as Cr, V, Zn, Ni, Pb, and Mo. We have studied the effects of the metals with different valence/charge on the metalloresistant Arthrobacter spp., the divalent cation—Zn(II) and the hexavalent anion—Cr(VI). The permanent presence of a nontoxic concentration of zinc alone or zinc together with the subtoxic concentration of chromium at the growth of A. oxydans and A. globiformis as batch culture causes the activation of the zinc primary uptake system transporters from the ZIP family (Zrt1). Chromium does not affect the process. The studied Arthrobacter spp. differ by the character of the activation of the antioxidant defense system. Chromium and zinc concomitant action causes the strongest oxidative stress in the case of A. globiformis that is demonstrated by the increased activity of superoxide dismutase (SOD) and catalase. In the case of A. oxydans, the zinc separate action, and the joint action of zinc and chromium decreases the activity of SOD and catalase. The antioxidant system is active in A. globiformis at the prolonged action of metals (96 h), whereas the cells of A. oxyidans activate the other defense mechanisms to survive.

NtZIP11, a new Zn transporter specifically upregulated in tobacco leaves by toxic Zn level

Understanding the molecular mechanisms governing the uptake and accumulation of Zn in the leaves of tobacco plants exposed to high Zn concentrations is important from the perspective of phytoremediation of metal contaminated soil. This study identifies a new candidate gene, NtZIP11, which may contribute to Zn accumulation in tobacco leaves. NtZIP11 encodes a protein of 346 amino acids, with characteristic conserved sequences of the ZIP family of proteins. Phylogenetic analysis shows that NtZIP11 forms a distinct clade with other ZIP11 proteins. Transient expression of GFP-tagged ZIP11 in the abaxial epidermis of tobacco leaves demonstrates localization at the plasma membrane. Yeast complementation tests and growth assays indicate that NtZIP11 is involved in Zn but not Fe, Mn and Cd uptake. NtZIP11 complements the zrt1zrt2 mutant deficient in Zn uptake, but not the fet3fet4 mutant deficient in Fe uptake. Nor does it modify the sensitivity of wild-type yeast, DY1457, to increasing concentrations of Fe, Mn and Cd. NtZIP11 is expressed in both roots and leaves, with transcript abundance increasing with age. Noteworthy, the expression level of NtZIP11 is not modulated by Zn-deficiency but is highly upregulated especially in the older leaves by high Zn concentrations (50 and 200 μM). Our data indicate that the primary role for NtZIP11 is in the uptake of Zn by the cells of tobacco leaves specifically when experiencing high Zn concentrations. It also likely contributes to maintaining a basal supply of Zn to cells at the level of the whole plant. Thus the present study contributes to broadening our understanding of Zn homeostasis mechanisms in tobacco, and clarifying the role of ZIP11 genes.

The trafficking of metal ion transporters of the Zrt- and Irt-like protein family.

Metal ion transporters of the Zrt- and Irt-like protein (ZIP, or SLC39A) family transport zinc, iron, manganese and/or cadmium across cellular membranes and into the cytosol. The 14 human ZIP family proteins are expressed in a wide variety of tissues and function in many different cellular processes. Many of these proteins (including ZIP1, 2, 3, 4, 5, 6/10, 8, 9, 11, 12, 14) are situated, at least some of the time, on the plasma membrane, where they mediate metal ion uptake into cells. Their level on the cell surface can be controlled rapidly via protein trafficking in response to the ions they transport. For example, the cell surface level of many ZIPs (including ZIP1, 3, 4, 8 and 12) is mediated by the available concentration of zinc. Zinc depletion causes a decrease in endocytosis and degradation, resulting in more ZIP on the surface to take up the essential ion. ZIP levels on the cell surface are a balance between endocytosis, recycling and degradation. We review the trafficking mechanisms of human ZIP proteins, highlighting possible targeting motifs and suggesting a model of zinc-mediated endocytic trafficking. We also provide two possible models for ZIP14 trafficking and degradation.

Prolonged stimulation of insulin release from MIN6 cells causes zinc depletion and loss of β-cell markers

Zinc is integral for the normal function of pancreatic β-cells in glycaemic control. Large amounts of zinc are secreted from β-cells following insulin exocytosis and regulated replenishment is required, which is thought to be mediated by the ZIP family of zinc importer proteins. Within Type 2 Diabetic patients, β-cells are stressed through prolonged stimulation by hyperglycaemia and this is thought to be a major factor contributing to loss of β-cell identity and mass. However, the consequences for the β-cell zinc status remain largely unexplored. We used inductively coupled plasma mass spectrometry (ICP-MS) to show that 24 h treatment of MIN6 cells with potassium chloride, mimicking hyperglycaemic stimulation, reduces the total cellular zinc content 2.8-fold, and qPCR to show an increase in mRNA expression for metallothioneins (Mt1 and Mt2) following 4 and 24 h of stimulation, suggestive of an early rise in cytosolic zinc. To determine which ZIP paralogues may be responsible for zinc replenishment, we used immunocytochemistry, Western blot and qPCR to demonstrate initial ZIP1 protein upregulation proceeded by downregulation of mRNA coding for ZIP1, ZIP6, ZIP7 and ZIP14. To assign a biological significance to the decreased total cellular zinc content, we assessed expression of key β-cell markers to show downregulation of mRNA for MafA, Mnx-1, Nkx2.2 and Pax6. Our data suggest hyperglycaemia-induced zinc depletion may contribute to loss of β-cell markers and promote β-cell dedifferentiation through disrupting expression of key transcription factors.

ZIP13: A Study of Drosophila Offers an Alternative Explanation for the Corresponding Human Disease.

The fruit fly Drosophila melanogaster has become an important model organism to investigate metal homeostasis and human diseases. Previously we identified dZIP13 (CG7816), a member of the ZIP transporter family (SLC39A) and presumably a zinc importer, is in fact physiologically primarily responsible to move iron from the cytosol into the secretory compartments in the fly. This review will discuss the implication of this finding for the etiology of Spondylocheirodysplasia-Ehlers-Danlos Syndrome (SCD–EDS), a human disease defective in ZIP13. We propose an entirely different model in that lack of iron in the secretory compartment may underlie SCD-EDS. Altogether three different working models are discussed, supported by relevant findings made in different studies, with uncertainties, and questions remained to be solved. We speculate that the distinct ZIP13 sequence features, different from those of all other ZIP family members, may confer it special transport properties.

Progress in ZIP transporter gene family in rice.

Zinc and iron are essential mineral elements for the growth of Oryza sativa L. and also micronutrients for human health. Therefore, it is vital to study biofortification of rice with Zn and Fe in order to improve the yield and quality of rice, as well as to enhance nutritional states of humans. The zinc-regulated transporters and iron-regulated transporter-like proteins (the ZIP family) control the absorption and translocation of Zn and Fe and maintain their homeostasis in rice. Reciprocally, the expression of the ZIP family is induced by the concentration of Zn and Fe. There are abundant natural allelic variations of the ZIP genes, and some haplotypes only occur in indica or japonica, which could affect Zn and Fe accumulation levels between these subspecies. Currently, emerging functional studies of the accumulation mechanism of Zn and Fe in grains reveal that a lot still needs to be learned about the allele variations of ZIP genes. In fact, only OsZIP3 is functional characterized. In this review, we summarize the latest progress in the molecular characteristics of the ZIP transporters, including protein localization, gene expression patterns, transport mechanism, metal ion interaction, and natural allelic variations.

Nanocarrier-mediated foliar zinc fertilization influences expression of metal homeostasis related genes in flag leaves and enhances gluten content in durum wheat.

BackgroundWheat is the staple food for most of the world’s population; however, it is a poor source of zinc. Foliar fertilization of zinc via zinc loaded chitosan nanocarriers (Zn-CNP) post-anthesis has proved to be a promising approach for grain zinc enhancement in durum wheat as evidenced in our earlier study. However, the molecular mechanism of uptake of zinc via Zn-CNP remains unclear.Methods/Principle findingsFoliar application of Zn-CNP was performed at post anthesis stages in two durum wheat cultivars (MACS 3125 and UC1114, containing the Gpc-B1 gene), and expression levels of several metal-related genes were analyzed during early senescence. Zn-CNP application indeed caused changes in gene expression as revealed by qPCR data on representative genes involved in metal homeostasis, phloem transporters, and leaf senescence. Furthermore, zinc-regulated transporters and iron (Fe)-regulated transporter-like protein (ZIP) family [ZIP1, ZIP7, ZIP15], CA (carbonic anhydrase), and DMAS (2’-deoxymugineic acid synthase) in flag leaves exhibited significant correlation with zinc content in the seeds. The analysis of grain endosperm proteins showed enhancement of gamma gliadins while other gluten subunits decreased. Gene expression within ZIP family members varied with the type of cultivar mostly attributed to the Gpc-B1, concentration of external zinc ions as well as the type of tissue analyzed. Correlation analysis revealed the involvement of the selected genes in zinc enhancement.ConclusionAt the molecular level, uptake of zinc via Zn-CNP nanocarrier was comparable to the uptake of zinc via common zinc fertilizers i.e. ZnSO4.

Developing gene-tagged molecular marker for functional analysis of OsZIP10 metal transporter gene in rice

The physiological, genetic and molecular mechanisms of metal homeostasis related genes need to be characterized from a bio-fortification perspective and should be well integrated with the breeding processes. Out of 43 genes related to metal homeostasis, transcript of OsZIP10 gene found to be associated with grain zinc content in rice. OsZIP10 gene belongs to ZIP family and is identified to encode a plasma membrane-localized zinc transporter in rice. In the present study, through allele mining identified a 10 bp insertion/deletion (InDel) polymorphism in the 5’upstream region of the gene. Targeting the InDel region five gene tagged markers were developed, named ZP1, ZP2, ZP3, ZP4, ZP5. The markers were validated in a set of selected rice genotypes contrasting for grain zinc content. Single marker analysis for allelic variation revealed significant association of markers with the phenotypic data (R2 value 0.39). The gene-tagged markers developed in the present study would be useful in breeding for enhanced grain zinc content in rice.

Nickel hyperaccumulation mechanisms: a review on the current state of knowledge

Hyperaccumulator plants are unusual plants that accumulate particular metals or metalloids, such as nickel, zinc, cadmium and arsenic, in their living tissues to concentrations that are hundreds to thousands of times greater than what is normal for most plants. The hyperaccumulation phenomenon is rare (exhibited by less than 0.2% of all angiosperms), with most of the ~500 hyperaccumulator species known globally for nickel. This review highlights the contemporary understanding of nickel hyperaccumulation processes, which include root uptake and sequestration, xylem loading and transport, leaf compartmentation and phloem translocation processes. Hyperaccumulator plants have evolved highly efficient physiological mechanisms for taking up nickel in their roots followed by rapid translocation and sequestration into the aerial shoots. The uptake of nickel is mainly involved with low affinity transport systems, presumably from the ZIP family. The presence of high concentrations of histidine prevents nickel sequestration in roots. Nickel is efficiently loaded into the xylem, where it mainly presents as Ni2+. The leaf is the main storage organ, which sequestrates nickel in non-active sites, e.g. vacuoles and apoplast. Recent studies show that phloem translocates high levels of nickel, which has a strong impact on nickel accumulation in young growing tissues.

Elemental Ingredients in the Macrophage Cocktail: Role of ZIP8 in Host Response to Mycobacterium tuberculosis.

Tuberculosis (TB) is a global epidemic caused by the infection of human macrophages with the world’s most deadly single bacterial pathogen, Mycobacterium tuberculosis (M.tb). M.tb resides in a phagosomal niche within macrophages, where trace element concentrations impact the immune response, bacterial metal metabolism, and bacterial survival. The manipulation of micronutrients is a critical mechanism of host defense against infection. In particular, the human zinc transporter Zrt-/Irt-like protein 8 (ZIP8), one of 14 ZIP family members, is important in the flux of divalent cations, including zinc, into the cytoplasm of macrophages. It also has been observed to exist on the membrane of cellular organelles, where it can serve as an efflux pump that transports zinc into the cytosol. ZIP8 is highly inducible in response to M.tb infection of macrophages, and we have observed its localization to the M.tb phagosome. The expression, localization, and function of ZIP8 and other divalent cation transporters within macrophages have important implications for TB prevention and dissemination and warrant further study. In particular, given the importance of zinc as an essential nutrient required for humans and M.tb, it is not yet clear whether ZIP-guided zinc transport serves as a host protective factor or, rather, is targeted by M.tb to enable its phagosomal survival.

Research progress on Zn transporter family SLC39A/ZIP and tumors

As an essential trace element for human, Zn is involved in the synthesis of various enzymes, and plays important roles in the growth and proliferation of cells. At the cellular level, Zn2+ homeostasis is maintained through the complex mechanisms of uptake, storage and excretion, where the Zn transporter families play certain roles. Two major Zn transporter families, namely the SLC30 (ZnT) family and the SLC39 (ZIP) family, have been identified, which act to control the intra- and extracellular equilibrium of Zn2+ . While the ZnT fa-mily mainly transports Zn out of the cells, while the ZIP family mainly contributes to the uptake and transport of Zn into the cells. The ZIP family has been noted to be associated with various diseases, and be closely related to the development and progression of tumors. Recent studies have suggested low ZIP1 and ZIP2 expression in prostate cancer, high ZIP6, ZIP7 and ZIP10 expression in breast cancer, high ZIP3 and ZIP4 expression in pancreatic cancer, and high ZIP5 and ZIP6 expression in esophageal cancer. The ZIP family may, therefore, function as tumor suppressor genes in prostate cancer, and oncogenes in pancreatic cancer, breast cancer and esophageal cancer. This paper reviews the latest research progress on SLC39 transporter family and tumors. Key words: Zinc; Zinc transporter; Cancer