Table 3.

ZIP transporters: location and regulation

Transporter	Tissue and cellular distribution	Stimulus	Response	Putative mechanism of response
ZIP1	Ubiquitous, [69] Plasma membrane [44] Intracellular vesicles [69]	Zinc deficiency in vitro [70]	Increased mouse ZIP1 protein expression in transfected Human embryonic kidney cells (HEK293) [70] (ZIP1 expression was unaffected by zinc in vivo [71])	Reduced rates of ZIP1 endocytosis due to zinc limitation [70]. Endocytosis of ZIP1 mediated through a di-leucine sorting signal [72]
		Cell differentiation of pluripotent mesenchymal stem cells into osteoblast-like cells [73]	Increased ZIP1 protein expression [73]	–
ZIP2	Dendritic cells, ovaries, skin, liver [79] Plasma membrane [79]	Reduced intracellular zinc in monocytes [44, 74]	Upregulation of ZIP2 mRNA in monocytes [44, 74]	–
		Granulocyte macrophage-colony stimulating factor in macrophages [44]	Upregulation of ZIP2 mRNA in macrophages [44]	–
		Keratinocyte differentiation [44]	Upregulation of ZIP2 mRNA in differentiating keratinocytes [44]	–
		Macrophage polarisation to M2 [75]	Increased ZIP2 mRNA levels [75]	–
ZIP3	Widespread [69] Plasma membrane but can localise to intracellular compartments after zinc treatment [44]	Zinc deficiency in zebrafish gill [76]	Increased ZIP3 mRNA [76]	–
		Zinc deficiency in vitro [70]	Increased cell surface mouse ZIP3 expression in transfected cells [70]	Reduced rates of ZIP3 endocytosis due to zinc limitation [70]
		Prolactin in secretory mammary epithelial cells [77]	Upregulation of ZIP3 mRNA and protein levels [77]	–
ZIP4	Small intestine and epidermis [79] Plasma membrane [79]	Cytosolic zinc excess [28, 44]	Downregulation of ZIP4 protein [44]	Endocytosis and degradation ubiquitin-proteasomal and lysosomal degradation pathways [44] Zinc repletion can lead to endocytosis and degradation of ZIP4 and ZIP4 mRNA destabilisation [71]
		Zinc deficiency [28, 44]	Upregulation of ZIP4 [28, 44]	Non-transcriptional: ZIP4 mRNA stabilisation [44] Transcriptional: Transcriptional upregulation mediated by Krüppel-like factor 4 (KLF4) [43, 78] Post-translational modification: Proteolytic cleavage of extracellular amino-terminal ectodomain [28, 43, 44]
ZIP5	Intestine, kidney, liver and pancreas [69, 79] Plasma membrane [43, 79]	Zinc availability in mice [44, 80]	Upregulation of ZIP5 translation [44, 80]	Facilitated by a conserved stem-loop and two overlapping miRNA seed sites in the 3’-untranslated region [44, 80]
		Dietary zinc deficiency in mice [71]	Downregulation of ZIP5 translation [71]	ZIP5 mRNA is associated with polysomes and ZIP5 protein is endocytosed and degraded in enterocytes, acinar cells, and endoderm cells [71]
ZIP6	Widespread [69, 79] Plasma membrane [44]	Lipopolysaccharide in dendritic cells [46]	Downregulation of ZIP6 mRNA expression [46]	Mediated through Toll/interleukin-1 receptor (TRIF) in Toll like receptor (TLR) signalling [46]
		Lipopolysaccharide in mice liver [59]	Increased ZIP6 mRNA [59]	–
		Macrophage polarisation to M2 [75]	Increased ZIP6 mRNA [75]	–
ZIP7	Widespread [69, 79]. Colon, skin [79] Endoplasmic reticulum and golgi apparatus [44]	Supplemental zinc [43]	Protein abundance of ZIP7 repressed by supplemental zinc [43]	–
		Cellular zinc levels [81]	ZIP7 expression inversely correlate with cellular zinc levels in CLN6 neurons [81]
		Macrophage polarisation to M2 [75]	Increased ZIP7 mRNA levels [75]	–
ZIP8	Widespread [69, 79, 82], T-cells [69], highest levels in the lung [82] Plasma membrane (apical in polarised cells) and lysosome [44]	T-cell activation in vitro [83]	Upregulation of ZIP8 expression in human T-cells [83]	–
		Lipopolysaccharide in primary human lung epithelia, monocytes and macrophages [84]	Upregulation of ZIP8 at transcriptional level [84]	NF-κB-dependent mechanism [84]
		TNF-alpha in primary human lung epithelia, monocytes and macrophages [84]	Upregulation of ZIP8 at transcriptional level [84]	NF-κB-dependent mechanism [84]
		Iron loading in rat H4IIE hepatoma cells [85]	Increase in total and cell surface ZIP8 levels [85]	–
ZIP9	Widely distributed [79] Plasma membrane, golgi apparatus [44]	Macrophage polarisation to M2 [75]	Increased ZIP9 mRNA levels [75]	–
ZIP10	Brain, liver, erythroid cell, kidney [69], renal cell, carcinoma B cell [79] Plasma membrane [43]	Zinc deficiency in zebrafish gill [76] Zinc excess in vitro and in vivo [76]	Upregulation of ZIP10 mRNA [76] Downregulation of ZIP10 mRNA [76]	MTF-1 was suggested to be a negative regulator of ZIP10 expression [76]
		Zinc deficiency in mice brain and liver [86]	Upregulation of ZIP10 transcription [86]	During zinc sufficient conditions, zinc-activated MTF-1 physically blocks Pol II movement through the gene, leading to ZIP10 transcription downregulation [86]
		Lipopolysaccharide in dendritic cells [46]	Downregulation of ZIP10 mRNA transcript expression [46]	Mediated through Toll/interleukin-1 receptor (TRIF) in Toll-like receptor (TLR) signalling [46]
		Cytokines in early B cell developmental stages [87]	Upregulated ZIP10 transcription [87]	JAK/STAT pathway involving two STAT binding sites in the promoter [87]
		Thyroid hormone in intestine and kidney cells in a rat model of hypo- and hyperthyroidism [88]	Increased ZIP10 mRNA and protein levels in hyperthyroid rats and decreased ZIP10 mRNA in hypothyroid rats, when compared to euthyroid rats [88]	–
ZIP11	Suggested to localise to stomach and colon [82] Nucleus, intracellular vesicles and plasma membrane of stomach and colon, golgi in mammary epithelial cells [44, 82]	Possibly zinc-dependent [89]	ZIP11 expression only modestly decreased in mouse stomach but not large or small intestine in response to dietary zinc deficiency. Upon acute zinc repletion, expression levels were not restored [89]	The presence of many MREs upstream of the first exon of the ZIP11 gene would suggest that ZIP11 expression is upregulated in response to increasing zinc levels; however, this was not seen in practice [44]
ZIP12	Brain [69, 79, 82], testis and retina [69], pulmonary vascular smooth muscle [79] Plasma membrane [44]	Hypoxia in pulmonary vascular smooth muscle cells [90]	Upregulation of ZIP12 mRNA expression [90]	The Slc39a12 gene contains a hypoxia response element (HRE) encoding HIF-1α- and HIF-2α-binding motifs and is located 1 kb downstream of the ZIP12 transcription start site [90]
ZIP13	Widespread [69], hard and connective tissues [79], golgi apparatus, and cytoplasmic vesicles [44]	High iron levels in Drosophila [91]	Upregulation of Drosophila ZIP13 levels [91]	Iron stabilises Drosophila ZIP13 protein, protecting it from degradation [91]
ZIP14	Widespread, liver, bone, and cartilage [79] Plasma membrane [44], endosome [79]	Zinc deficiency in mouse liver [92]	Upregulation of ZIP14 expression [92]	Mediated through the UPR [92]
		IL-6 in mouse hepatocytes [59]	Increased ZIP14 mRNA and protein [59]	–
		Inflammation induced by turpentine [59]	Increased ZIP14 mRNA [59]	Requires IL-6 [59, 93]
		Lipopolysaccharide in mice liver [59]	Increased ZIP14 mRNA [59]	Partially requires IL-6 [59, 93]
		Nitric oxide (induced by IL-1β) in mice liver [93]	Increased ZIP14 transcription [93]	Nitric oxide increases binding of Activator Protein-1 (AP-1) to the ZIP14 promoter [93]
		High manganese intake in mice [67]	Upregulated liver ZIP14 expression in both male and female mice, but upregulated small intestine ZIP14 expression only in male mice [67]	–
		High extracellular glucose (medium) involving INS-1E cells [94]	Upregulation of ZIP14 mRNA expression [94]	–
		Iron loading in rat liver and pancreas, and in hypotransferrinemic mice liver [95]	Upregulated ZIP14 protein expression [95]	–