Abstract
Zinc is an essential nutrient for all organisms. Its requirement in humans is illustrated dramatically by the genetic disorder acrodermatitis enteropathica (AE). AE is caused by the reduced uptake of dietary zinc by enterocytes, and the ensuing systemic zinc deficiency leads to dermatological lesions and immune and reproductive dysfunction. The gene responsible for AE, SLC39A4, encodes a member of the ZIP family of metal transporters, hZIP4. The mouse ZIP4 protein, mZIP4, stimulates zinc uptake in cultured cells, and studies in mice have demonstrated that zinc treatment decreases mZIP4 mRNA levels in the gut. In this study, we demonstrated using transfected cultured cells that the mZIP4 protein is also regulated at a post-translational level in response to zinc availability. Zinc deficiency increased mZIP4 protein levels at the plasma membrane, and this was associated with increased zinc uptake. Significantly, treating cells with low micromolar zinc concentrations stimulated the rapid endocytosis of the transporter. Zinc-regulated localization of the human ZIP4 protein was also demonstrated in cultured cells. These findings suggest that zinc-regulated trafficking of human and mouse ZIP4 is a key mechanism controlling dietary zinc absorption and cellular zinc homeostasis.
Highlights
Zinc is an essential nutrient for all organisms because it is required by a variety of enzymes that are involved in critical areas of metabolism
The primary basis of acrodermatitis enteropathica (AE) is hypothesized to be the reduced uptake of dietary zinc by intestinal cells [15, 16] because patients respond positively to dietary zinc supplements [11, 12, 17, 18]. Consistent with this hypothesis was the finding that the affected protein in AE, hZIP4, and the murine homolog, mZIP4, are most abundantly expressed in the small intestine [8], and the mZIP4 protein is located at the apical membrane of intestinal enterocytes in zinc-deficient mice [8, 19]
Studies using mice have established that mZIP4 mRNA levels in the small intestine and embryonic visceral yolk sac are induced under conditions of dietary zinc deficiency, suggesting that the transcription or stability of mZIP4 mRNA is regulated by zinc availability [19]
Summary
Zinc is an essential nutrient for all organisms because it is required by a variety of enzymes that are involved in critical areas of metabolism. 14 ZIP proteins have been identified by data base sequence comparisons [5], and at least two of these proteins, hZIP1 and hZIP2, function as zinc importers when expressed in K562 cells [6, 7]. The primary basis of AE is hypothesized to be the reduced uptake of dietary zinc by intestinal cells [15, 16] because patients respond positively to dietary zinc supplements [11, 12, 17, 18] Consistent with this hypothesis was the finding that the affected protein in AE, hZIP4, and the murine homolog, mZIP4, are most abundantly expressed in the small intestine [8], and the mZIP4 protein is located at the apical membrane of intestinal enterocytes in zinc-deficient mice [8, 19].
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