The Functions of Metallothionein and ZIP and ZnT Transporters: An Overview and Perspective

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2016 Mar 10

PMID 26959009

Citations 180

Authors

Tomoki Kimura

Taiho Kambe

Affiliations

Soon will be listed here.

Abstract

Around 3000 proteins are thought to bind zinc in vivo, which corresponds to ~10% of the human proteome. Zinc plays a pivotal role as a structural, catalytic, and signaling component that functions in numerous physiological processes. It is more widely used as a structural element in proteins than any other transition metal ion, is a catalytic component of many enzymes, and acts as a cellular signaling mediator. Thus, it is expected that zinc metabolism and homeostasis have sophisticated regulation, and elucidating the underlying molecular basis of this is essential to understanding zinc functions in cellular physiology and pathogenesis. In recent decades, an increasing amount of evidence has uncovered critical roles of a number of proteins in zinc metabolism and homeostasis through influxing, chelating, sequestrating, coordinating, releasing, and effluxing zinc. Metallothioneins (MT) and Zrt- and Irt-like proteins (ZIP) and Zn transporters (ZnT) are the proteins primarily involved in these processes, and their malfunction has been implicated in a number of inherited diseases such as acrodermatitis enteropathica. The present review updates our current understanding of the biological functions of MTs and ZIP and ZnT transporters from several new perspectives.

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References

Ehret G, Munroe P, Rice K, Bochud M, Johnson A, Chasman D . Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011; 478(7367):103-9. PMC: 3340926. DOI: 10.1038/nature10405. View

Inoue K, Matsuda K, Itoh M, Kawaguchi H, Tomoike H, Aoyagi T . Osteopenia and male-specific sudden cardiac death in mice lacking a zinc transporter gene, Znt5. Hum Mol Genet. 2002; 11(15):1775-84. DOI: 10.1093/hmg/11.15.1775. View

Yoshida M, Ohta H, Yamauchi Y, Seki Y, Sagi M, Yamazaki K . Age-dependent changes in metallothionein levels in liver and kidney of the Japanese. Biol Trace Elem Res. 1998; 63(2):167-75. DOI: 10.1007/BF02778875. View

Saxena R, Voight B, Lyssenko V, Burtt N, de Bakker P, Chen H . Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007; 316(5829):1331-6. DOI: 10.1126/science.1142358. View

Aydemir T, Chang S, Guthrie G, Maki A, Ryu M, Karabiyik A . Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia). PLoS One. 2012; 7(10):e48679. PMC: 3480510. DOI: 10.1371/journal.pone.0048679. View

Boycott K, Beaulieu C, Kernohan K, Gebril O, Mhanni A, Chudley A . Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8. Am J Hum Genet. 2015; 97(6):886-93. PMC: 4678439. DOI: 10.1016/j.ajhg.2015.11.002. View

KAGI J, VALEE B . Metallothionein: a cadmium- and zinc-containing protein from equine renal cortex. J Biol Chem. 1960; 235:3460-5. View

Hirako N, Nakano H, Takahashi S . A PU.1 suppressive target gene, metallothionein 1G, inhibits retinoic acid-induced NB4 cell differentiation. PLoS One. 2014; 9(7):e103282. PMC: 4114787. DOI: 10.1371/journal.pone.0103282. View

Kelleher S, Lopez V, Lonnerdal B, Dufner-Beattie J, Andrews G . Zip3 (Slc39a3) functions in zinc reuptake from the alveolar lumen in lactating mammary gland. Am J Physiol Regul Integr Comp Physiol. 2009; 297(1):R194-201. PMC: 2711697. DOI: 10.1152/ajpregu.00162.2009. View

10.

Nakane H, Hirano M, Ito H, Hosono S, Oze I, Matsuda F . Impact of metallothionein gene polymorphisms on the risk of lung cancer in a Japanese population. Mol Carcinog. 2014; 54 Suppl 1:E122-8. DOI: 10.1002/mc.22198. View

11.

Wimmer U, Wang Y, Georgiev O, Schaffner W . Two major branches of anti-cadmium defense in the mouse: MTF-1/metallothioneins and glutathione. Nucleic Acids Res. 2005; 33(18):5715-27. PMC: 1253828. DOI: 10.1093/nar/gki881. View

12.

Colvin R, Holmes W, Fontaine C, Maret W . Cytosolic zinc buffering and muffling: their role in intracellular zinc homeostasis. Metallomics. 2010; 2(5):306-17. DOI: 10.1039/b926662c. View

13.

Kambe T, Hashimoto A, Fujimoto S . Current understanding of ZIP and ZnT zinc transporters in human health and diseases. Cell Mol Life Sci. 2014; 71(17):3281-95. PMC: 11113243. DOI: 10.1007/s00018-014-1617-0. View

14.

Kimura T, Itoh N, Takehara M, Oguro I, Ishizaki J, Nakanishi T . Sensitivity of metallothionein-null mice to LPS/D-galactosamine-induced lethality. Biochem Biophys Res Commun. 2001; 280(1):358-62. DOI: 10.1006/bbrc.2000.4085. View

15.

Kambe T, Weaver B, Andrews G . The genetics of essential metal homeostasis during development. Genesis. 2008; 46(4):214-28. PMC: 2366893. DOI: 10.1002/dvg.20382. View

16.

Schmitt S, Kury S, Giraud M, Dreno B, Kharfi M, Bezieau S . An update on mutations of the SLC39A4 gene in acrodermatitis enteropathica. Hum Mutat. 2009; 30(6):926-33. DOI: 10.1002/humu.20988. View

17.

Hamza I, Faisst A, Prohaska J, Chen J, Gruss P, Gitlin J . The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis. Proc Natl Acad Sci U S A. 2001; 98(12):6848-52. PMC: 34441. DOI: 10.1073/pnas.111058498. View

18.

Palmiter R . Constitutive expression of metallothionein-III (MT-III), but not MT-I, inhibits growth when cells become zinc deficient. Toxicol Appl Pharmacol. 1995; 135(1):139-46. DOI: 10.1006/taap.1995.1216. View

19.

Peters J, Dufner-Beattie J, Xu W, Geiser J, Lahner B, Salt D . Targeting of the mouse Slc39a2 (Zip2) gene reveals highly cell-specific patterns of expression, and unique functions in zinc, iron, and calcium homeostasis. Genesis. 2007; 45(6):339-52. DOI: 10.1002/dvg.20297. View

20.

Rao S, Procko E, Shannon M . Chromatin remodeling, measured by a novel real-time polymerase chain reaction assay, across the proximal promoter region of the IL-2 gene. J Immunol. 2001; 167(8):4494-503. DOI: 10.4049/jimmunol.167.8.4494. View