Zn2+-stimulated endocytosis of the mZIP4 zinc transporter regulates its location at the plasma membrane.
Zinc is an essential nutrient for all organisms. Its requirement in humans is illustrated dramatically by the genetic disorder acrodermatitis enteropathica (AE). AE is caused by the reduced uptake of dietary zinc by enterocytes, and the ensuing systemic zinc deficiency leads to dermatological lesions and immune and reproductive dysfunction. The gene responsible for AE, SLC39A4, encodes a member of the ZIP family of metal transporters, hZIP4. The mouse ZIP4 protein, mZIP4, stimulates zinc uptake in cultured cells, and studies in mice have demonstrated that zinc treatment decreases mZIP4 mRNA levels in the gut. In this study, we demonstrated using transfected cultured cells that the mZIP4 protein is also regulated at a post-translational level in response to zinc availability. Zinc deficiency increased mZIP4 protein levels at the plasma membrane, and this was associated with increased zinc uptake. Significantly, treating cells with low micromolar zinc concentrations stimulated the rapid endocytosis of the transporter. Zinc-regulated localization of the human ZIP4 protein was also demonstrated in cultured cells. These findings suggest that zinc-regulated trafficking of human and mouse ZIP4 is a key mechanism controlling dietary zinc absorption and cellular zinc homeostasis.
Kim
Byung-Eun
BE
Departments of Nutritional Sciences and Biochemistry, University of Missouri, Columbia, Missouri 65211, USA.
Wang
Fudi
F
Dufner-Beattie
Jodi
J
Andrews
Glen K
GK
Eide
David J
DJ
Petris
Michael J
MJ
D000818:Animals; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004705:Endocytosis; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015032:Zinc / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology
D027682:Cation Transport Proteins; D011993:Recombinant Fusion Proteins; C486791:SLC39A4 protein, human; C477530:Slc39a4 protein, mouse; D015032:Zinc