Dataset Information

The metal transporter ZIP13 supplies iron into the secretory pathway in Drosophila melanogaster.

ABSTRACT: The intracellular iron transfer process is not well understood, and the identity of the iron transporter responsible for iron delivery to the secretory compartments remains elusive. In this study, we show Drosophila ZIP13 (Slc39a13), a presumed zinc importer, fulfills the iron effluxing role. Interfering with dZIP13 expression causes iron-rescuable iron absorption defect, simultaneous iron increase in the cytosol and decrease in the secretory compartments, failure of ferritin iron loading, and abnormal collagen secretion. dZIP13 expression in E. coli confers upon the host iron-dependent growth and iron resistance. Importantly, time-coursed transport assays using an iron isotope indicated a potent iron exporting activity of dZIP13. The identification of dZIP13 as an iron transporter suggests that the spondylocheiro dysplastic form of Ehlers-Danlos syndrome, in which hZIP13 is defective, is likely due to a failure of iron delivery to the secretory compartments. Our results also broaden our knowledge of the scope of defects from iron dyshomeostasis.

SUBMITTER: Xiao G

PROVIDER: S-EPMC4130162 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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The metal transporter ZIP13 supplies iron into the secretory pathway in Drosophila melanogaster.

Xiao Guiran G Wan Zhihui Z Fan Qiangwang Q Tang Xiaona X Zhou Bing B

eLife 20140708

The intracellular iron transfer process is not well understood, and the identity of the iron transporter responsible for iron delivery to the secretory compartments remains elusive. In this study, we show Drosophila ZIP13 (Slc39a13), a presumed zinc importer, fulfills the iron effluxing role. Interfering with dZIP13 expression causes iron-rescuable iron absorption defect, simultaneous iron increase in the cytosol and decrease in the secretory compartments, failure of ferritin iron loading, and a ...[more]

PMID: 25006035

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Project description:eLife digestIron is essential for life. Amongst its many important roles, iron is crucial for producing collagen—the protein that provides both strength and elasticity to bones, tendons, ligaments, and skin. Like many other proteins, collagens are produced inside the endoplasmic reticulum—an organelle inside the cell that is enclosed by a membrane that is similar to the plasma membrane that surrounds the cell itself.Two enzymes that are critical for producing collagen need to bind with iron in order to work correctly. To do this, iron in the cytoplasm of the cell has to cross the membrane that surrounds the endoplasmic reticulum. Small molecules are commonly transported across membranes by proteins called transporters, which tend to work on specific types of ions or molecules. However, researchers did not know the identity of the membrane transporter responsible for moving iron into the secretory pathway—including the endoplasmic reticulum—to bind with the enzymes that produce collagen.Xiao, Wan et al. have now investigated the function of the transporter ZIP13 in the fruit fly Drosophila. This transporter was thought to transport zinc across membranes and into the cytoplasm. Instead, Xiao, Wan et al. found that ZIP13 transports iron out of the cytoplasm and into the endoplasmic reticulum.Ehlers–Danlos syndrome is a condition that causes individuals to suffer from frequent joint dislocations, bone deformities, and fragile skin as a result of their body producing collagen incorrectly. One form of Ehlers–Danlos syndrome is caused by ZIP13 transporters working incorrectly. However, this was difficult to understand when it was thought that ZIP13 only transports zinc. The discovery that ZIP13 mostly transports iron rather than zinc can explain the link between this transporter and Ehlers–Danlos syndrome: if ZIP13 doesn't work, the collagen-building enzymes cannot get the iron they need to work properly.Disorders caused by iron deficiencies are normally identified by a few tell-tale symptoms, such as anemia, but these are not seen in Ehlers–Danlos syndrome. Xiao, Wan et al. suggest that iron transport problems could therefore be behind a wider range of diseases and disorders than is currently known.DOI: http://dx.doi.org/10.7554/eLife.03191.002

Project description:Lymphatic filariasis and onchocerciasis are neglected parasitic diseases which pose a threat to public health in tropical and sub-tropical regions. Strategies for control and elimination of these diseases by mass drug administration (MDA) campaigns are designed to reduce symptoms of onchocerciasis and transmission of both parasites to eventually eliminate the burden on public health. Drugs used for MDA are predominantly microfilaricidal, and prolonged rounds of treatment are required for eradication. Understanding parasite biology is crucial to unravelling the complex processes involved in host-parasite interactions, disease transmission, parasite immune evasion, and the emergence of drug resistance. In nematode biology, large gaps still exist in our understanding of iron metabolism, iron-dependent processes and their regulation. The acquisition of iron from the host is a crucial determinant of the success of a parasitic infection. Here we identify a filarial ortholog of Divalent Metal Transporter 1 (DMT1), a member of a highly conserved family of NRAMP proteins that play an essential role in the transport of ferrous iron in many species. We cloned and expressed the B. malayi NRAMP ortholog in the iron-deficient fet3fet4 strain of Saccharomyces cerevisiae, performed qPCR to estimate stage-specific expression, and localized expression of this gene by immunohistochemistry. Results from functional iron uptake assays showed that expression of this gene in the iron transport-deficient yeast strain significantly rescued growth in low-iron medium. DMT1 was highly expressed in adult female and male B. malayi and Onchocerca volvulus. Immunolocalization revealed that DMT1 is expressed in the intestinal brush border, lateral chords, and reproductive tissues of males and females, areas also inhabited by Wolbachia. We hypothesize based on our results that DMT1 in B. malayi functions as an iron transporter. The presence of this transporter in the intestine supports the hypothesis that iron acquisition by adult females requires oral ingestion and suggests that the intestine plays a functional role in at least some aspects of nutrient uptake.

Dataset Information

The metal transporter ZIP13 supplies iron into the secretory pathway in Drosophila melanogaster.

Publications

The metal transporter ZIP13 supplies iron into the secretory pathway in Drosophila melanogaster.

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