A role for the Drosophila zinc transporter Zip88E in protecting against dietary zinc toxicity

Abstract

Zinc absorption in animals is thought to be regulated in a local, cell autonomous manner with intestinal cells responding to dietary zinc content. The Drosophila zinc transporter Zip88E shows strong sequence similarity to Zips 42C.1, 42C.2 and 89B as well as mammalian Zips 1, 2 and 3, suggesting that it may act in concert with the apically-localised Drosophila zinc uptake transporters to facilitate dietary zinc absorption by importing ions into the midgut enterocytes. However, the functional characterisation of Zip88E presented here indicates that Zip88E may instead play a role in detecting and responding to zinc toxicity. Larvae homozygous for a null Zip88E allele are viable yet display heightened sensitivity to elevated levels of dietary zinc. This decreased zinc tolerance is accompanied by an overall decrease in Metallothionein B transcription throughout the larval midgut. A Zip88E reporter gene is expressed only in the salivary glands, a handful of enteroendocrine cells at the boundary between the anterior and middle midgut regions, and in two parallel strips of sensory cell projections connecting to the larval ventral ganglion. Zip88E expression solely in this restricted subset of cells is sufficient to rescue the Zip88E mutant phenotype. Together, our data suggest that Zip88E may be functioning in a small subset of cells to detect excessive zinc levels and induce a systemic response to reduce dietary zinc absorption and hence protect against toxicity.

Anatomy and Physiology of the Digestive Tract of Drosophila melanogaster

“…Zip88E was also once thought to contribute to the dietary absorption of zinc ( Dechen et al 2015 ). However, the recent generation of a Zip88E-Gal4 reporter is suggestive of expression in subsets of neurons and EE cells, pointing to possible roles in metal sensing or transport these cell subsets ( Richards et al 2017 ).…”

Copper and Zinc Homeostasis: Lessons from Drosophila melanogaster

“…dZip88E was initially thought to be the fourth member of this group formed by dZip42C.1, dZip42C.2, and dZip89B to absorb Zn from diet (Lye et al, 2012 ). However, its recent characterization (Richards et al, 2017 ) and the results from genetic interactions (Dechen et al, 2015 ), suggest a completely different role. It is expressed in a small subset of cells in the gut and larval CNS displaying both, plasma membrane and intracellular localization (Dechen et al, 2015 ; Richards et al, 2017 ).…”

“…However, its recent characterization (Richards et al, 2017 ) and the results from genetic interactions (Dechen et al, 2015 ), suggest a completely different role. It is expressed in a small subset of cells in the gut and larval CNS displaying both, plasma membrane and intracellular localization (Dechen et al, 2015 ; Richards et al, 2017 ). Interestingly, even with this restrictive expression, mutant flies are hypersensitive toward Zn.…”

Biogenesis of zinc storage granules inDrosophila melanogaster

“…MTF-1 also regulates the ferritin subunit genes, for reasons that are unclear (Yepiskoposyan et al, 2006;Gutiérrez et al, 2010Gutiérrez et al, , 2013. Little is known about the mechanism of zinc homeostasis in the organism as a whole (Richards et al, 2017), particularly how zinc is stored in Drosophila (Schofield et al, 1997).…”