Drosophila fear of intimacy Encodes a Zrt/IRT-like Protein (ZIP) Family Zinc Transporter Functionally Related to Mammalian ZIP Proteins

Abstract

Zinc is essential for many cellular processes, and its concentration in the cell must be tightly controlled. The Zrt/IRT-like protein (ZIP) family of zinc transporters have recently been identified as the main regulators of zinc influx into the cytoplasm (1); however, little is known about their in vivo roles. Previously, we have shown that fear of intimacy (foi) encodes a putative member of the ZIP family that is essential for development in Drosophila (2). Here we demonstrate that FOI can act as an ion transporter in both yeast and mammalian cell assays and is specific for zinc. We also provide insight into the mechanism of action of the ZIP family through membrane topology and structure-function analyses of FOI. Our work demonstrates that Drosophila FOI is closely related to mammalian ZIP proteins at the functional level and that Drosophila represents an ideal system for understanding the in vivo roles of this family. In addition, this work indicates that the control of zinc by ZIP transporters may play a critical role in regulating developmental processes.

In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion

“…In the other two models, the presence of seven transmembrane domains implies that N-and C-termini are not located at the same side of plasma membrane. Our experimental data are in accordance with most of predicted models and consistent with the zinc export (Mathews et al, 2005). Furthermore, this membrane topology of zinc export transporter is also consistent with a role for ZnT-8 in exporting zinc from the cytoplasm to insulin-containing vesicles.…”

Systematic functional characterization of putative zinc transport genes and identification of zinc toxicosis phenotypes inDrosophila melanogaster

“…Secondary X-ray fluorescence and scattering was collected using a 384-element Maia detector, which was oriented in back scatter geometry to the beam. The Journal of Experimental Biology 215 (18) et al, 2006), whilst FOI has been shown to take up zinc through the outer plasma membrane in yeast and mammalian cell culture assays (Mathews et al, 2005). Note that while we have retained the long-held names for Catsup and foi, for the remaining 15 genes we have adopted the nomenclature of Yepiskoposyan (Yepiskoposyan et al, 2006), calling each gene dZnT or dZip followed by the gene's cytological location.…”

“…Copper-related phenotypes that result from overexpression or suppression of important copper transport genes, such as DmATP7 and Ctr1a, commonly result in abnormal pigment phenotypes, neuronal defects and impaired survival when larvae and adults are reared on modulated copper diets (Binks et al, 2010;Burke et al, 2008;Norgate et al, 2006). In addition to the previously characterized Drosophila zinc transport genes ZnT35c (Yepiskoposyan et al, 2006), dZnT63C (Wang et al, 2009), fear of intimacy (foi) (Mathews et al, 2006;Mathews et al, 2005) and Catchecholamines up (Catsup) (Stathakis et al, 1999), nine more putative zinc transport genes were identified for analysis during this study with an additional four being recently identified by homology to mammalian proteins. Thus, with 17 predicted zinc transport genes compared with the 25 in mammals, the Drosophila system is clearly still complex yet has reduced scope for redundancy compared with higher organisms and, more importantly, provides rapid and flexible gene manipulation tools for sophisticated in vivo functional analyses.…”

Zinc supplement greatly improves the condition of parkin mutant Drosophila

“…More than 10 zinc transporter genes are annotated in Drosophila melanogaster based on their sequence similarities to vertebrate zinc transporters. The ZIP family gene foi (fear of intimacy) was characterized in Drosophila and shown to be a zinc importer that is critical during development (Moore et al, 1998;Mathews et al, 2005). Transcriptional responses to zinc in Drosophila larvae were analyzed in our laboratory (Yepiskoposyan et al, 2006).…”

“…The elevated metallothionein levels could also explain at least in part why an increased zinc concentration is not toxic to the parkin mutants. We also determined the transcript levels of three zinc transporters, the exporters ZnT35C and ZnT63C and the importer foi (Mathews et al, 2005;Yepiskoposyan et al, 2006) both in parkin mutants and in the heterozygous controls. The most conspicuous difference was observed with the exporter gene ZnT35C, a known target of MTF-1.…”