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

abstract: ...Background Zinc 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 . Results A 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. Conclusions Our 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.

... possible roles in dietary zinc absorption in a genetically amenable model organism, Drosophila melanogaster . Results A 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

... 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. Conclusions Our 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

.... Although some analyses of dZips and dZnTs have been undertaken [ 17 , 38 , 39 ], none of these transporters, except for dZnT1 [ 31 ], have been studied for their involvement or regulation in the process of dietary zinc absorption. Results Identification of two close homologs, dZip1 and dZip2, as specific zinc transporters involved in dietary zinc absorption We previously demonstrated that dZnT1 is involved in the efflux of zinc from the midgut enterocytes for systemic use. However, it was not known

... knocked down, either ubiquitously or gut-specifically, only around 10 to 15% of the larvae survived to adulthood on a zinc-limited diet (0.3mmol/l EDTA-supplemented food) whereas the eclosion of the control flies was only slightly affected under the same conditions (Figure 1 A; see Additional file 1 : Figure S1C), suggesting that CG9430 is indispensable for proper zinc uptake. Figure 1 Drosophila Zip1 (dZip1) and dZip2 are zinc-specific transporters involved in dietary zinc absorption. (A) Gut-specific knockdown of dZip2 or of dZip1 dZip2 in combination resulted in impaired larval development under zinc deficiency (0.3mmol/l EDTA). (B) Reverse transcriptase (RT)-PCR analysis of the knockdown effect of the dZip1 -RNAi and dZip2 -RNAi lines. rp49 was used as the loading control. (C) Ubiquitous knockdown of either dZip1 or dZip2 produced a reduction in alkaline phosphatase (ALP) activity but did not affect aconitase activity. (D) Gut-specific knockdown of either dZip1 or dZip2 similarly led to reduced ALP activity of whole body minus gut in flies fed on 0.1mmol/l EDTA-supplemented food. (E) dZip2 -RNAi and dZip1 - , dZip2 -RNAi flies are specifically sensitive to zinc deficiency. The survival rate of these RNAi flies on EDTA-supplemented food could be rescued by adding back zinc but not other metals. (A,D) Genotypes of flies used were NP3084/+ , NP3084/+; dZip1 -RNAi/ + ( dZip1 -RNAi fly), NP3084/+; dZip2 -RNAi/ + ( dZip2 -RNAi fly), NP3084/+; dZip1-, dZip2 -RNAi/ + ( dZip1-, dZip2 -RNAi fly). (B,C,E) Genotypes of flies used were da-GAL4/+ for control and da-GAL4/dZip1 -RNAi for dZip1 -RNAi, da-GAL4/dZip2 -RNAi for dZip2 -RNAi, and da-GAL4/dZip- dZip2 -RNAi for the double RNAi fly. Values are presented as meansSEM; n3. * P <0.05, ** P <0.01, *** P <0.001; one-way ANOVA. The protein encoded by CG9430 shows high homology (28% identity and 50% similarity) to human Zip1 and Zip2 (hZip1 and hZip2). Interestingly, an immediately adjacent gene in this genomic region, CG9428, is very

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Gene: DZIP1 - DAZ interacting zinc finger protein 1 - (NCBI)

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