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

Bowers, Katherine; Srai, Surjit Kaila

doi:10.1111/tra.12602

Cited by 44 publications

(37 citation statements)

References 98 publications

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“…1a, right panel). Placement of ZIP14 at the basolateral membrane is consistent with its function as a hepatocyte metal importer (Bowers and Srai 2018;Guthrie et al 2015;Pinilla-Tenas et al 2011;Zhao et al 2014).…”

Section: Resultssupporting

confidence: 53%

ZIP14 is degraded in response to manganese exposure

Thompson

Wessling‐Resnick

2019

Biometals

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Manganese (Mn) is an essential element necessary for proper development and brain function. Circulating Mn levels are regulated by hepatobiliary clearance to limit toxic levels and prevent tissue deposition. To characterize mechanisms involved in hepatocyte Mn uptake, polarized human HepaRG cells were used for this study. Western blot analysis and immunofluorescence microscopy showed the Mn transporter ZIP14 was expressed and localized to the basolateral surface of polarized HepaRG cells. HepaRG cells took up 54Mn in a time- and temperature-dependent manner but uptake was reduced after exposure to Mn. This loss in transport activity was associated with decreased ZIP14 protein levels in response to Mn exposure. Mn-induced degradation of ZIP14 was blocked by bafilomycin A1, which increased localization of the transporter in Lamp1-positive vesicles. Mn exposure also down-regulated the Golgi proteins TMEM165 and GPP130 while the ER stress marker BiP was induced. These results indicate that Mn exposure decreases ZIP14 protein levels to limit subsequent uptake of Mn as a cytoprotective response. Thus, high levels of Mn may compromise first-pass-hepatic clearance mechanisms.

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Section: Resultssupporting

confidence: 53%

ZIP14 is degraded in response to manganese exposure

Thompson

Wessling‐Resnick

2019

Biometals

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“…Sequence comparison of the 14 hZIPs showed that only hZIP12, which is the closest homolog of hZIP4, has a conserved “ 509 IQL” motif in the corresponding cytosolic loop, suggesting that the other hZIPs expressed at the plasma membrane may use distinct motifs for sorting, such as a dileucine motif in ZIP1 ( Huang and Kirschke, 2007 ), if they are similarly internalized upon zinc repletion. Markedly, the L2 is the most divergent segment in the TMD among the hZIPs, supporting a notion that this least conserved loop is a key element in specific regulation for each ZIP protein ( Bafaro et al, 2015 ; Bowers and Srai, 2018 ).…”

Section: Discussionmentioning

confidence: 59%

Molecular Basis of Zinc-Dependent Endocytosis of Human ZIP4 Transceptor

et al. 2020

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SUMMARY Nutrient transporters can be rapidly removed from the cell surface via substrate-stimulated endocytosis as a way to control nutrient influx, but the molecular underpinnings are not well understood. In this work, we focus on zinc-dependent endocytosis of human ZIP4 (hZIP4), a zinc transporter that is essential for dietary zinc uptake. Structure-guided mutagenesis and internalization assay reveal that hZIP4 per se acts as the exclusive zinc sensor, with the transport site’s being responsible for zinc sensing. In an effort of seeking sorting signal, a scan of the longest cytosolic loop (L2) leads to identification of a conserved Leu-Gln-Leu motif that is essential for endocytosis. Partial proteolysis of purified hZIP4 demonstrates a structural coupling between the transport site and the L2 upon zinc binding, which supports a working model of how zinc ions at physiological concentration trigger a conformation-dependent endocytosis of the zinc transporter. This work provides a paradigm on post-translational regulation of nutrient transporters.

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“…Kordas and Stoltzfus [341] showed that althoughFedoes seem to reduce the absorption ofZn, DMT-1 is an unlikely site for this absorptive antagonism because Znis not transported by DMT-1. Zrt-and Irt-like protein-14 (Zip14) is a transmembrane metal iron transporter that is abundantly expressed in the liver, heart, and pancreas [342].…”

Section: Fe Vs Znmentioning

confidence: 99%

The Role of Fe, Zn, and Cu in Pregnancy

2020

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Iron (Fe), copper (Cu), and zinc (Zn) are microelements essential for the proper functioning of living organisms. These elements participatein many processes, including cellular metabolism and antioxidant and anti-inflammatory defenses, and also influence enzyme activity, regulate gene expression, and take part in protein synthesis. Fe, Cu, and Zn have a significant impact on the health of pregnant women and in the development of the fetus, as well as on the health of the newborn. A proper concentration of these elements in the body of women during pregnancy reduces the risk of complications such as anemia, induced hypertension, low birth weight, preeclampsia, and postnatal complications. The interactions between Fe, Cu, and Zn influence their availability due to their similar physicochemical properties. This most often occurs during intestinal absorption, where metal ions compete for binding sites with transport compounds. Additionally, the relationships between these ions have a great influence on the course of reactions in the tissues, as well as on their excretion, which can be stimulated or delayed. This review aims to summarize reports on the influence of Fe, Cu, and Zn on the course of single and multiple pregnancies, and to discuss the interdependencies and mechanisms occurring between Fe, Cu, and Zn.

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

Cited by 44 publications

References 98 publications

ZIP14 is degraded in response to manganese exposure

ZIP14 is degraded in response to manganese exposure

Molecular Basis of Zinc-Dependent Endocytosis of Human ZIP4 Transceptor

The Role of Fe, Zn, and Cu in Pregnancy

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