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

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      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.

      DOI: http://dx.doi.org/10.7554/eLife.03191.001

      eLife digest

      Iron 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

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      Most cited references 47

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      A protein trap strategy to detect GFP-tagged proteins expressed from their endogenous loci in Drosophila.

      In Drosophila, enhancer trap strategies allow rapid access to expression patterns, molecular data, and mutations in trapped genes. However, they do not give any information at the protein level, e.g., about the protein subcellular localization. Using the green fluorescent protein (GFP) as a mobile artificial exon carried by a transposable P-element, we have developed a protein trap system. We screened for individual flies, in which GFP tags full-length endogenous proteins expressed from their endogenous locus, allowing us to observe their cellular and subcellular distribution. GFP fusions are targeted to virtually any compartment of the cell. In the case of insertions in previously known genes, we observe that the subcellular localization of the fusion protein corresponds to the described distribution of the endogenous protein. The artificial GFP exon does not disturb upstream and downstream splicing events. Many insertions correspond to genes not predicted by the Drosophila Genome Project. Our results show the feasibility of a protein trap in Drosophila. GFP reveals in real time the dynamics of protein's distribution in the whole, live organism and provides useful markers for a number of cellular structures and compartments.
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        Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter.

        Defects in iron absorption and utilization lead to iron deficiency and overload disorders. Adult mammals absorb iron through the duodenum, whereas embryos obtain iron through placental transport. Iron uptake from the intestinal lumen through the apical surface of polarized duodenal enterocytes is mediated by the divalent metal transporter, DMTi. A second transporter has been postulated to export iron across the basolateral surface to the circulation. Here we have used positional cloning to identify the gene responsible for the hypochromic anaemia of the zebrafish mutant weissherbst. The gene, ferroportin1, encodes a multiple-transmembrane domain protein, expressed in the yolk sac, that is a candidate for the elusive iron exporter. Zebrafish ferroportin1 is required for the transport of iron from maternally derived yolk stores to the circulation and functions as an iron exporter when expressed in Xenopus oocytes. Human Ferroportin1 is found at the basal surface of placental syncytiotrophoblasts, suggesting that it also transports iron from mother to embryo. Mammalian Ferroportin1 is expressed at the basolateral surface of duodenal enterocytes and could export cellular iron into the circulation. We propose that Ferroportin1 function may be perturbed in mammalian disorders of iron deficiency or overload.
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          Collagens, modifying enzymes and their mutations in humans, flies and worms.

          Collagens and proteins with collagen-like domains form large superfamilies in various species, and the numbers of known family members are increasing constantly. Vertebrates have at least 27 collagen types with 42 distinct polypeptide chains, >20 additional proteins with collagen-like domains and approximately 20 isoenzymes of various collagen-modifying enzymes. Caenorhabditis elegans has approximately 175 cuticle collagen polypeptides and two basement membrane collagens. Drosophila melanogaster has far fewer collagens than many other species but has approximately 20 polypeptides similar to the catalytic subunits of prolyl 4-hydroxylase, the key enzyme of collagen synthesis. More than 1300 mutations have so far been characterized in 23 of the 42 human collagen genes in various diseases, and many mouse models and C. elegans mutants are also available to analyse the collagen gene family and their modifying enzymes.
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            Author and article information

            Affiliations
            deptState Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences , Tsinghua University , Beijing, China
            Howard Hughes Medical Institute, University of California, Berkeley , United States
            Howard Hughes Medical Institute, University of California, Berkeley , United States
            Author notes
            [* ]For correspondence: zhoubing@ 123456mail.tsinghua.edu.cn
            [†]

            These authors contributed equally to this work.

            Contributors
            Role: Reviewing editor,
            Howard Hughes Medical Institute, University of California, Berkeley , United States
            Journal
            eLife
            eLife
            eLife
            eLife
            eLife Sciences Publications, Ltd
            2050-084X
            08 July 2014
            2014
            : 3
            25006035 4130162 03191 10.7554/eLife.03191
            © 2014, Xiao et al

            This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

            Product
            Funding
            Funded by: National Basic Research Program of China;
            Award ID: 2013CB910700, 2011CB910900
            Award Recipient :
            Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
            Award ID: 31123004
            Award Recipient :
            The funder had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
            Categories
            Research Article
            Cell Biology
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            2
            Drosophila ZIP13 (Slc39a13), a presumed zinc importer, is responsible for iron delivery to the secretory pathway.

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