Zinc- and bicarbonate-dependent ZIP8 transporter mediates selenite uptake

McDermott, Joseph; Geng, Xiangrong; Jiang, Lan; Gálvez-Peralta, Marina; Chen, Fei; Nebert, Daniel W.; Liu, Zijuan

doi:10.18632/oncotarget.9205

Cited by 25 publications

(21 citation statements)

References 46 publications

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“…Iron and zinc inhibit the ZIP8-mediated uptake of one another [40, 42, 43]. Therefore, these cations have the potential to modulate the impact of zinc on macrophage immune function through competitive uptake and cell signaling [44, 45].…”

Section: Resultsmentioning

confidence: 99%

Zinc Modulates Endotoxin-Induced Human Macrophage Inflammation through ZIP8 Induction and C/EBPβ Inhibition

et al. 2017

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Two vital functions of the innate immune system are to initiate inflammation and redistribute micronutrients in favor of the host. Zinc is an essential micronutrient used in host defense. The zinc importer ZIP8 is uniquely induced through stimulation of the NF-κB pathway by LPS in monocytes and functions to regulate inflammation in a zinc-dependent manner. Herein we determined the impact of zinc metabolism following LPS-induced inflammation in human macrophages. We observed that ZIP8 is constitutively expressed in resting macrophages and strikingly elevated following LPS exposure, a response that is unique compared to the 13 other known zinc import proteins. During LPS exposure, extracellular zinc concentrations within the physiological range markedly reduced IL-10 mRNA expression and protein release but increased mRNA expression of TNFα, IL-8, and IL-6. ZIP8 knockdown inhibited LPS-driven cellular accumulation of zinc and prevented zinc-dependent reduction of IL-10 release. Further, zinc supplementation reduced nuclear localization and activity of C/EBPβ, a transcription factor known to drive IL-10 expression. These studies demonstrate for the first time that zinc regulates LPS-mediated immune activation of human macrophages in a ZIP8-dependent manner, reducing IL-10. Based on these findings we predict that macrophage zinc metabolism is important in host defense against pathogens.

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Section: Resultsmentioning

confidence: 99%

Zinc Modulates Endotoxin-Induced Human Macrophage Inflammation through ZIP8 Induction and C/EBPβ Inhibition

et al. 2017

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“…Zrt/Irt-like protein 8 (ZIP8) is a multifunctional membrane transporter protein that facilitates uptake of several essential and nonessential divalent metals, including Zn 2ϩ , Mn 2ϩ , and Fe 2ϩ (15,18,34,57). More recently, ZIP8 was found to be a major transporter of inorganic selenite (HSeO 3 Ϫ ); transport of selenite requires both Zn 2ϩ and bicarbonate as cosubstrates (41). ZIP8 substrates Zn 2ϩ , Mn 2ϩ , Fe 2ϩ , and selenite are critically required in maintaining normal cellular function.…”

Section: Introductionmentioning

confidence: 99%

Hepatic ZIP8 deficiency is associated with disrupted selenium homeostasis, liver pathology, and tumor formation

Liu

Geng

Cai

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Zrt/Irt-like protein 8 (ZIP8) (encoded by Slc39a8) is a multifunctional membrane transporter that influxes essential metal cations Zn, Mn, Fe, and nonmetal inorganic selenite (HSeO). 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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“…Cation transport by ZIP8 is pH dependent and electroneutral, indicating that it facilitates the co-transport of other ionic species as well [ 47 , 69 , 71 ]. ZIP8 participates in the cytosolic influx of manganese, cadmium, iron, zinc, and selenite [ 71 , 77 ]. Iron and zinc inhibit the ZIP8-mediated uptake of each other [ 69 ].…”

Section: Zip8 In Macrophage Infection By Mtbmentioning

confidence: 99%

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

Pyle

Azad

Papp

et al. 2017

IJMS

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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.

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Zinc- and bicarbonate-dependent ZIP8 transporter mediates selenite uptake

Cited by 25 publications

References 46 publications

Zinc Modulates Endotoxin-Induced Human Macrophage Inflammation through ZIP8 Induction and C/EBPβ Inhibition

Zinc Modulates Endotoxin-Induced Human Macrophage Inflammation through ZIP8 Induction and C/EBPβ Inhibition

Hepatic ZIP8 deficiency is associated with disrupted selenium homeostasis, liver pathology, and tumor formation

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

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