Novel zinc-responsive post-transcriptional mechanisms reciprocally regulate expression of the mouse Slc39a4 and Slc39a5 zinc transporters (Zip4 and Zip5)

Abstract

Dietary zinc deficiency in mice is accompanied by enhanced expression of the zinc uptake transporter Slc39a4 (Zip4) and repressed expression of Slc39a5 (Zip5) in tissues which regulate zinc homeostasis (intestine, pancreas and visceral yolk sac). Herein, mechanisms controlling this differential expression were investigated. The induction of Zip4 mRNA during zinc deficiency, and its repression in response to zinc repletion were found to reflect changes in Zip4 mRNA stability and not changes in the relative rate of transcription of this gene. During zinc deficiency, ZIP4 protein levels are increased and this protein is localized on the apical membranes. Administration of an oral gavage of zinc caused ZIP4 internalization and degradation in enterocytes and visceral endoderm cells. Similarly, ZIP4 is induced by zinc deficiency in cultured mouse Hepa cells and is rapidly degraded in response to added zinc. Zip5 mRNA abundance does not change in response to zinc, but the translation of this mRNA was found to be zinc-responsive. During zinc deficiency, Zip5 mRNA remains associated with polysomes, while the protein is internalized and degraded in enterocytes, acinar cells and endoderm cells. After zinc-gavage, ZIP5 is rapidly resynthesized and targeted to the basolateral membranes of these cell types.

Krüppel-like factor 4 regulates adaptive expression of the zinc transporterZip4in mouse small intestine

“…In contrast to our data with intact mice and mouse IECs, others have presented evidence interpreted to indicate that Zip4 is controlled through mRNA stability, rather than changes in transcription (35). Those interpretations may reflect the fact that the bulk of the experiments were conducted with cell lines that are nonintestinal in origin and, hence, do not express large amounts of Zip4.…”

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

“…The overexpressed ZIP1 on the cell surface is endocytosed, thereby decreasing in response to excess zinc (429), which is mediated through the dileucine motif in the cytosolic loop between TM helices III and IV (168). ZIP1 expression, however, is not zinc responsive in vivo (437) …”

“…Most ZIP transporters are localized to the plasma membrane, and their cell-surface localization, except for ZIP5, increases under zinc-deficient conditions (56,85,116,161,207,241,246,249,402,431). Rapid internalization and degradation occurs to these transporters in response to excess zinc (168, 261,437). There are no three-dimensional structures of ZIP transporters and their homologs.…”

<i>In Vitro</i> Study on the Transport of Zinc across Intestinal Epithelial Cells Using Caco-2 Monolayers and Isolated Rat Intestinal Membranes

“…During dietary zinc deficiency, ZIP5 is internalized to undergo degradation. 12,28) Under zinc-depleted condition, ZIP5 carries zinc into enterocytes from blood and then excretes zinc into the intestinal lumen. ZIP5 has been reported to play a central role in mammalian zinc homeostasis by antagonizing the actions of ZIP4.…”