Skip to content
University of Maryland LibrariesDigital Repository at the University of Maryland
    • Login
    View Item 
    •   DRUM
    • Theses and Dissertations from UMD
    • UMD Theses and Dissertations
    • View Item
    •   DRUM
    • Theses and Dissertations from UMD
    • UMD Theses and Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    MRP5/ABCC5, A CONSERVED ABC TRANSPORTER, REGULATES METAZOAN HEME HOMEOSTASIS

    Thumbnail
    View/Open
    Korolnek_umd_0117E_15447.pdf (4.720Mb)
    No. of downloads: 528

    Date
    2014
    Author
    Korolnek, Tamara
    Advisor
    Hamza, Iqbal
    DRUM DOI
    https://doi.org/10.13016/M2K592
    Metadata
    Show full item record
    Abstract
    Hemes are metalloporphyrins used by nearly all organisms as cofactors for proteins involved in respiration, binding and sensing gases, and as catalysts for various reactions. Despite extensive knowledge about heme biosynthesis and catabolism, the pathways for transporting heme between cells and within cells remain poorly understood. C. elegans serves as a unique animal model for uncovering these pathways, as it is unable to synthesize its own heme and depends on the uptake of dietary heme for growth and reproduction. Functional RNAi screens implicated mrp-5 as a potential heme transporter in C. elegans. This gene encodes a membrane-bound ABC transporter that localizes to the basolateral intestinal membrane and is required for worm growth and reproduction. Depletion of mrp-5 activates heme deprivation signals within the worm, protects worms from toxicity associated with a toxic heme analog, and results in worms accumulating the fluorescent heme analog, zinc mesoporphyrin IX, in intestinal cells. Taken together, these results indicate a defect in heme export from the intestine when MRP-5 activity is lost. Functional assays in yeast support the hypothesis that MRP-5 is capable of exporting heme across cell membranes, and that this function is conserved in the human ortholog. Knockdown of mrp5 in zebrafish embryos results in developmental defects and decreased blood formation, indicating that this transporter likely regulates heme homeostasis in vertebrates. Loss of Mrp5 in mammalian cells leads to decreased heme transport into the secretory pathway as measured by activity of a Golgi-targeted heme-dependent enzyme. Furthermore, macrophages from mice lacking Mrp5 are unable to activate a number of cellular responses when undergoing erythrophagocytosis, the process whereby the heme-iron in senescent red bloods is recycled. Altogether, our results implicate MRP-5 as a key heme transporter in C. elegans, and point to an evolutionarily conserved role for MRP5 proteins in regulating heme homeostasis.
    URI
    http://hdl.handle.net/1903/15744
    Collections
    • Cell Biology & Molecular Genetics Theses and Dissertations
    • UMD Theses and Dissertations

    DRUM is brought to you by the University of Maryland Libraries
    University of Maryland, College Park, MD 20742-7011 (301)314-1328.
    Please send us your comments.
    Web Accessibility
     

     

    Browse

    All of DRUMCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

    My Account

    LoginRegister
    Pages
    About DRUMAbout Download Statistics

    DRUM is brought to you by the University of Maryland Libraries
    University of Maryland, College Park, MD 20742-7011 (301)314-1328.
    Please send us your comments.
    Web Accessibility