The acrodermatitis enteropathica gene ZIP4 encodes a tissue-specific, zinc-regulated zinc transporter in mice.
The human ZIP4 gene (SLC39A4) is a candidate for the genetic disorder of zinc metabolism acrodermatitis enteropathica. To understand its role in zinc homeostasis, we examined the function and expression of mouse ZIP4. This gene encodes a well conserved eight-transmembrane protein that can specifically increase the influx of zinc into transfected cells. Expression of this gene is robust in tissues involved in nutrient uptake, such as the intestines and embryonic visceral yolk sac, and is dynamically regulated by zinc. Dietary zinc deficiency causes a marked increase in the accumulation of ZIP4 mRNA in these tissues, whereas injection of zinc or increasing zinc content of the diet rapidly reduces its abundance. Zinc can also regulate the accumulation of ZIP4 protein at the apical surface of enterocytes and visceral endoderm cells. These results provide compelling evidence that ZIP4 is a zinc transporter that plays an important role in zinc homeostasis, a process that is defective in acrodermatitis enteropathica in humans.
Dufner-Beattie
Jodi
J
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160-7421, USA.
Wang
Fudi
F
Kuo
Yien-Ming
YM
Gitschier
Jane
J
Eide
David
D
Andrews
Glen K
GK
D000169:Acrodermatitis / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D002412:Cations; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000196:embryology; D007700:Kinetics; D008297:Male; D008670:Metals / Q000737:chemistry; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution; D014162:Transfection; D015032:Zinc / Q000378:metabolism
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D002412:Cations; D008670:Metals; D010455:Peptides; D012333:RNA, Messenger; C486791:SLC39A4 protein, human; C477530:Slc39a4 protein, mouse; C017800:zinc-binding protein; D012313:RNA; D015032:Zinc