Molecular and pathophysiological aspects of metal ion uptake by the zinc transporter ZIP8 (SLC39A8 (original) (raw)
Related papers
Molecular insights of the human zinc transporter hZIP4
2016
Zinc is the second most abundant transition metal in the body. Despite the fact that hundreds of biomolecules require zinc for proper function and/or structure, the mechanism of zinc transport into cells is not well-understood. ZnT and ZIP proteins are members of the SoLute Carrier (SLC) family of membrane transporters and are one of the principal family of proteins involved in regulating intracellular zinc concentration. ZnT (Zinc Transporters) decrease the cytosolic concentration of zinc, while ZIP (for Zinc or Iron regulated Proteins) transporters function to increase the cytosolic zinc concentration. Mutations in one member of the ZIP family of proteins, the human ZIP4 (hZIP4; SLC39A4) protein, can result in the disease acrodermatitis enteropathica (AE). AE is characterized by growth retardation, diarrhea, behavioral disturbances and neurological disorders. While the cellular distribution of hZIP4 protein expression has been elucidated, the cation specificity, kinetic parameters of zinc transport, residues involved in cation translocation and structural details are unresolved questions.
Zinc fluxes and zinc transporter genes in chronic diseases
Mutation Research-fundamental and Molecular Mechanisms of Mutagenesis, 2007
The group IIb metal zinc (Zn) is an essential dietary component that can be found in protein rich foods such as meat, seafood and legumes. Thousands of genes encoding Zn binding proteins were identified, especially after the completion of genome projects, an indication that a great number of biological processes are Zn dependent. Imbalance in Zn homeostasis was found to be associated with several chronic diseases such as asthma, diabetes and Alzheimer's disease. As it is now evident for most nutrients, body Zn status results from the interaction between diet and genotype. Zn ions cross biological membranes with the aid of specialized membrane proteins, belonging to the ZRT/IRT-related Proteins (ZIP) and zinc transporters (ZnT) families. The ZIPs are encoded by the Slc39A gene family and are responsible for uptake of the metal, ZnTs are encoded by the Slc30A genes and are involved in intracellular traffic and/or excretion. Both ZnTs and Zips exhibit unique tissue-specific expression, differential responsiveness to dietary Zn deficiency and excess, as well as to physiological stimuli via hormones and cytokines. Intracellular Zn concentration is buffered by metallothioneins (MTs), a class of cytosolic protein with high affinity for metals. Scattered information is available on the role of proteins responsible for regulating Zn fluxes in the onset and progression of chronic diseases. This paper reviews reports that link Zn transporter genes, their allelic variants and/or expression profiles in the context of specific diseases. Further investigation in this direction is very important, since Zn imbalance can result not only from insufficient dietary intake, but also from impaired activity of proteins that regulate Zn metabolism, thus contributing to multifactorial diseases.
SLC39A8/ZIP8 Influences Complex Traits by Regulating Metal Ion Metabolism
2017
Common genetic variants at the SLC39A8 locus are genome-wide significantly associated with a variety of traits in human, and SLC39A8 loss-of-function results in developmental defects in multiple organs of both human and mice. SLC39A8 encodes ZIP8, a metal ion transporter best known for transporting manganese (Mn) and zinc (Zn), two essential nutrients required for general metabolism. The goal of my dissertation is to explore the mechanism in which SLC39A8 mediates metal ion transport in vivo and to test the hypothesis that SLC39A8 pleiotropically influences complex traits by regulating metal ion transport. I took advantage of novel Slc398a8 mouse models, cell lines, and samples from human carriers of an SLC39A8 variant. I discovered that hepatic Zip8 reclaims Mn from biliary excretion to maintain whole-body Mn homeostasis, and that hepatic Zip8 is a quantitative regulator of whole-body Mn. Slc39a8 deletion in mice leads to protein N-glycosylation defects indicative of decreased activity of a Mn-dependent enzyme, β-1, 4-galactosyltransferase, while homozygosity of a SLC39A8 loss-of-function variant is associated with hypogalactosylation, suggesting that protein N-glycosylation may be related to the association of SLC39A8 with complex traits in GWAS. Slc39a8 acts through Mn to quantitatively modulate the activity of arginase, another Mn-dependent enzyme that influences blood pressure via nitric oxide (NO). Slc39a8 deletion in mice results in increased NO production, decreased blood pressure, and protection against high-salt-induced hypertension, while homozygosity of the SLC39A8 loss-of-function variant in human is associated with increased NO, providing a plausible explanation for the association of SLC39A8 with blood pressure. Slc39a8 deletion in combination with a Zn deficient diet decrease HDL-C in the blood, suggesting Zn may be involved in the association of SLC39A8 with HDL-C. During embryonic development, Slc39a8 deletion in mice recapitulates hallmarks of left ventricular noncompaction, a rare cardiomyopathy in human. Mechanistically, Slc39a8 deletion decreases cellular Zn uptake, which leads to reduced metal-regulatory transcription factor 1 transcriptional activity, decreased Adamts metalloproteinase transcription, and impaired extracellular matrix degradation that has been implicated in noncompaction. Thus my dissertation reveals the mechanism in which Slc39a8 mediates Mn transport in vivo and demonstrates that Slc39a8 acts through Mn and Zn to modulate the activity of Mn and Zn-dependent enzymes and transcription factors, which in turn pleiotropically influence complex traits especially blood pressure and heart ventricle development.
Frontiers in Physiology
The metal ion transporter ZIP8 (SLC39A8) mediates cellular uptake of vital divalent metal ions. Genome-wide association studies (GWAS) showed that the single-nucleotide polymorphism (SNP) variant A391T (rs13107325) is associated with numerous human traits, including reduced arterial blood pressure, increased body mass index and hyperlipidemia. We analyzed in vitro the transport properties of mutant ZIP8 A391T and investigated in vivo in mice the physiological effects of this polymorphism. In vitro, the intrinsic transport properties of mutant ZIP8 were similar to those of wild type ZIP8, but cellular uptake of zinc, cadmium and iron was attenuated due to reduced ZIP8 plasma membrane expression. We then generated the ZIP8 A393T mice (ZIP8KI) that carry the corresponding polymorphism and characterized their phenotype. We observed lower protein expression in lung and kidney membrane extracts in ZIP8KI mice. The ZIP8KI mice exhibited striking changes in metal ion composition of the tiss...
The role of zinc transporters in cadmium and manganese transport in mammalian cells
Biochimie, 2009
To understand the mechanism of cadmium accumulation, it is important to know the precise mechanisms of transport systems for other metals. Recently, utilization of genomics and metallomics has clarified the involvement of specific metal transporter(s) in cadmium uptake. Studies with metallothionein (MT)-null cadmium-resistant cells have revealed the involvement of the manganese/zinc transport system in cadmium uptake. Genomic studies of strain differences in sensitivity to cadmiuminduced testicular hemorrhage revealed that a zinc transporter, Zrt-, Irt-related protein (ZIP) 8 encoded by slc39a8, is responsible for the strain difference. Ectopic expression of ZIP8 in various cells enhanced the uptake of cadmium, manganese, and zinc. ZIP8-transgenic mice showed high expression of ZIP8 in the vasculature of testis and apical membrane of proximal tubules in kidney, and exhibited enhanced cadmium accumulation and toxicity when treated with cadmium. The expression of ZIP8 was found to be down-regulated in MT-null cadmium-resistant cells, in which the uptake rates of both cadmium and manganese were decreased. These data suggest that ZIP8 plays an important role in the uptake of both cadmium and manganese in mammalian cells. The role of ZIP14 in the uptake of cadmium and manganese is also discussed.
Journal of Nutrition, 2011
The zinc transporter (ZnT; SLC30) and Zrt-and Irt-like protein (Zip, SLC39) zinc transporter families are integral to the maintenance of intracellular zinc concentrations. Few studies have examined the expression patterns of zinc transporter genes in human primary tissues. This study investigated the expression levels of a range of zinc transporter mRNA in the peripheral blood mononuclear cells of healthy men and women (n = 40) using quantitative real-time PCR. It also explored the relationships among zinc transporter expression levels, plasma zinc concentrations, and dietary zinc intake. The relative expression of the zinc transporter mRNA varied considerably, with ZnT7, ZnT1, and Zip1 being the most abundantly expressed. ZnT1 and Zip1 mRNA were highly correlated with one another (r = 0.9; P , 0.001) and with ZnT5, ZnT7, Zip3, and Zip10 (P , 0.001). When analyzed by gender, a correlation between the mRNA of ZnT7 and Zip3 (r = 0.6; P , 0.01) was demonstrated only in women. Zip10 mRNA was correlated with ZnT1 and Zip1 (r = 0.9; P , 0.001) in men only. In a regression analysis, plasma zinc variability was not significantly explained by dietary zinc intake, gender, age, or any individual or combination of zinc transporters. This study expands what is known about both the levels of zinc transporter gene transcription in humans and the extent of its variation in healthy men and women. The positive association between the mRNA of ZnT1 and Zip1, which have reciprocal roles in zinc transport across the plasma membrane, provides insight into the coordinated control of zinc homeostasis in humans.
Cellular and Molecular Life Sciences, 2020
Zinc is required for the regulation of proliferation, metabolism, and cell signaling. It is an intracellular second messenger, and the cellular level of ionic, mobile zinc is strictly controlled by zinc transporters. In mammals, zinc homeostasis is primarily regulated by ZIP and ZnT zinc transporters. The importance of these transporters is underscored by the list of diseases resulting from changes in transporter expression and activity. However, despite numerous structural studies of the transporters revealing both zinc binding sites and motifs important for transporter function, the exact molecular mechanisms regulating ZIP and ZnT activities are still not clear. For example, protein phosphorylation was found to regulate ZIP7 activity resulting in the release of Zn 2+ from intracellular stores leading to phosphorylation of tyrosine kinases and activation of signaling pathways. In addition, sequence analyses predict all 24 human zinc transporters to be phosphorylated suggesting that protein phosphorylation is important for regulation of transporter function. This review describes how zinc transporters are implicated in a number of important human diseases. It summarizes the current knowledge regarding ZIP and ZnT transporter structures and points to how protein phosphorylation seems to be important for the regulation of zinc transporter activity. The review addresses the need to investigate the role of protein phosphorylation in zinc transporter function and regulation, and argues for a pressing need to introduce quantitative phosphoproteomics to specifically target zinc transporters and proteins involved in zinc signaling. Finally, different quantitative phosphoproteomic strategies are suggested.
Genes & Nutrition, 2015
The usefulness of zinc transporter and metallothionein (MT) gene expressions to detect changes in zinc intake remains unclear. This pilot study aimed to determine the effects of zinc supplementation on zinc transporter and MT gene expressions in humans. Healthy adults (n = 39) were randomised to zinc treatment (ZT), receiving 22 mg Zn/day (n = 19), or no treatment (NT) (n = 20). Blood samples were collected on Days 0, 2, 7, 14, and 21. Plasma zinc and serum C-reactive protein concentrations were analysed. Gene expression of zinc transporters and MT in peripheral blood mononuclear cells was analysed using real-time PCR. Using repeated-measures ANOVA, MT-2A gene expression and fold change were found to be higher in the ZT group (P = 0.025 and P = 0.016, respectively) compared to the NT group, specifically at Day 2 (40 ± 18 % increase from baseline, P = 0.011), despite no significant increase in plasma zinc concentration. In a multiple regression model exploring the changes in gene expressions between Days 0 and 21, the change in MT-2A gene expression was correlated with changes in all zinc transporter expressions (r 2 = 0.54, P = 0.029); the change in ZIP1 expression emerged as a univariate predictor (P = 0.003). Dietary zinc intake was predictive of zinc transporter and MT expressions (P = 0.030). Physical activity level was positively correlated with baseline ZIP7 expression (r = 0.36, P = 0.029). The present study shows that MT-2A expression is related to changing expression of zinc transporter genes, specifically ZIP1, in response to zinc supplementation. The current report adds to our understanding of MT in the coordinated nature of cellular zinc homeostasis.
MTF-1-mediated repression of the zinc transporter Zip10 is alleviated by zinc restriction
PloS one, 2011
The regulation of cellular zinc uptake is a key process in the overall mechanism governing mammalian zinc homeostasis and how zinc participates in cellular functions. We analyzed the zinc transporters of the Zip family in both the brain and liver of zinc-deficient animals and found a large, significant increase in Zip10 expression. Additionally, Zip10 expression decreased in response to zinc repletion. Moreover, isolated mouse hepatocytes, AML12 hepatocytes, and Neuro 2A cells also respond differentially to zinc availability in vitro. Measurement of Zip10 hnRNA and actinomycin D inhibition studies indicate that Zip10 was transcriptionally regulated by zinc deficiency. Through luciferase promoter constructs and ChIP analysis, binding of MTF-1 to a metal response element located 17 bp downstream of the transcription start site was shown to be necessary for zinc-induced repression of Zip10. Furthermore, zinc-activated MTF-1 causes down-regulation of Zip10 transcription by physically blocking Pol II movement through the gene. Lastly, ZIP10 is localized to the plasma membrane of hepatocytes and neuro 2A cells. Collectively, these results reveal a novel repressive role for MTF-1 in the regulation of the Zip10 zinc transporter expression by pausing Pol II transcription. ZIP10 may have roles in control of zinc homeostasis in specific sites particularly those of the brain and liver. Within that context ZIP10 may act as an important survival mechanism during periods of zinc inadequacy. Citation: Lichten LA, Ryu M-S, Guo L, Embury J, Cousins RJ (2011) MTF-1-Mediated Repression of the Zinc Transporter Zip10 Is Alleviated by Zinc Restriction. PLoS ONE 6(6): e21526.