Functional studies of Drosophilazinc transporters reveal the mechanism for dietary zinc absorption and regulation

Abstract

BackgroundZinc is key to the function of many proteins, but the process of dietary zinc absorption is not well clarified. Current knowledge about dietary zinc absorption is fragmented, and mostly derives from incomplete mammalian studies. To gain a comprehensive picture of this process, we systematically characterized all zinc transporters (that is, the Zip and ZnT family members) for their possible roles in dietary zinc absorption in a genetically amenable model organism, Drosophila melanogaster.ResultsA set of plasma membrane-resident zinc transporters was identified to be responsible for absorbing zinc from the lumen into the enterocyte and the subsequent exit of zinc to the circulation. dZip1 and dZip2, two functionally overlapping zinc importers, are responsible for absorbing zinc from the lumen into the enterocyte. Exit of zinc to the circulation is mediated through another two functionally overlapping zinc exporters, dZnT1, and its homolog CG5130 (dZnT77C). Somewhat surprisingly, it appears that the array of intracellular ZnT proteins, including the Golgi-resident dZnT7, is not directly involved in dietary zinc absorption. By modulating zinc status in different parts of the body, we found that regulation of dietary zinc absorption, in contrast to that of iron, is unresponsive to bodily needs or zinc status outside the gut. The zinc transporters that are involved in dietary zinc absorption, including the importers dZip1 and dZip2, and the exporter dZnT1, are respectively regulated at the RNA and protein levels by zinc in the enterocyte.ConclusionsOur study using the model organism Drosophila thus starts to reveal a comprehensive sketch of dietary zinc absorption and its regulatory control, a process that is still incompletely understood in mammalian organisms. The knowledge gained will act as a reference for future mammalian studies, and also enable an appreciation of this important process from an evolutionary perspective.

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

“…from the lumen into the enterocyte (257,336), and the imported zinc is released into circulation by dZnt1 (dZnT63C) and ZnT77C (CG5130, no vertebrate ZnT homologs) on the basolateral membrane (257,336). Gut-specific silencing of dZnt1 increases lethality under zinc-deficient conditions, which indicates importance of dZnt1 function on zinc absorption (433).…”

“…Gut-specific silencing of dZnt1 increases lethality under zinc-deficient conditions, which indicates importance of dZnt1 function on zinc absorption (433). Zinc repletion suppresses dZip1 and dZip2 mRNA expression and also suppresses dZnt1 protein expression (336). Expression of dZnt1 (dZnT63C) and dZnT35C (possibly a ZnT2 homolog) is regulated by dMTF1 (454).…”

Insects as sources of iron and zinc in human nutrition

“…These transporters are homologues to the human Zip (SLC39) and ZnT (SLC30) family members and are responsible for cellular influx and efflux, respectively. Zn transporters can be found ubiquitously or accumulated in specific organs/regions of the gastrointestinal tract, for example, the expression of dZip1 in the midgut and dZnT35C in the Malpighian tubules of D. melanogaster (40)(41)(42) that have roles in the absorption and excretion of Zn. Much less information is available on Zn storage in insects.…”

Compartmentalized zinc deficiency and toxicities caused by ZnT and Zip gene over expression result in specific phenotypes in Drosophila

“…We have previously carried out a preliminary functional characterization of most of the seventeen Drosophila dZip and dZnT genes (Lye et al, 2012) and in doing so, generated a zinc toxicity phenotype (Lye et al, 2013) by targeting over expression of the key Drosophila zinc uptake gene dZip42C.1 (dZip1, Qin et al, 2013) together with knockdown of the major zinc efflux gene, dZnT63C (dZnT1, Wang et al, 2009). This Ztox (zinc toxicity) combination behaved as expected if excess zinc ions were being trapped in the cytosol and was generally exacerbated by over expression of other dZip genes and rescued by over expression of other dZnT genes.…”