Control of metazoan heme homeostasis by a conserved multidrug resistance protein.
Several lines of evidence predict that specific pathways must exist in metazoans for the escorted movement of heme, an essential but cytotoxic iron-containing organic ring, within and between cells and tissues, but these pathways remain obscure. In Caenorhabditis elegans, embryonic development is inextricably dependent on both maternally derived heme and environmentally acquired heme. Here, we show that the multidrug resistance protein MRP-5/ABCC5 likely acts as a heme exporter, and targeted depletion of mrp-5 in the intestine causes embryonic lethality. Transient knockdown of mrp5 in zebrafish leads to morphological defects and failure to hemoglobinize red blood cells. MRP5 resides on the plasma membrane and endosomal compartments and regulates export of cytosolic heme. Together, our genetic studies in worms, yeast, zebrafish, and mammalian cells identify a conserved, physiological role for a multidrug resistance protein in regulating systemic heme homeostasis. We envision other MRP family members may play similar unanticipated physiological roles in animal development.
Department of Animal and Avian Sciences and Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
Tamara
T
Korolnek
Department of Animal and Avian Sciences and Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
Jianbing
J
Zhang
Department of Animal and Avian Sciences and Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
Simon
S
Beardsley
Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
George L
GL
Scheffer
Department of Animal and Avian Sciences and Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA. Electronic address: hamza@umd.edu.
Iqbal
I
Hamza
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004912:Erythrocytes / Q000473:pathology; D004913:Erythrocytes, Abnormal / Q000166:cytology; D004920:Erythropoiesis / Q000502:physiology*; D006418:Heme / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering; D015027:Zebrafish / Q000502:physiology
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D029742:Caenorhabditis elegans Proteins; D006418:Heme; D008565:Membrane Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D034741:RNA, Small Interfering; C000598558:MRP-5 protein, C elegans