title: A histidine-rich cluster mediates the ubiquitination and degradation of the human zinc transporter, hZIP4, and protects against zinc cytotoxicity.
abstract: Zinc is an essential nutrient. Genetic evidence for this nutritional requirement in humans is the zinc deficiency disease, acrodermatitis enteropathica. This disorder is caused by mutations in hZIP4 (SLC39A4), a zinc importer required for zinc uptake in enterocytes and other cell types. Studies in mice have demonstrated that levels of the mZIP4 mRNA are reduced by elevated dietary zinc, resulting in a decreased abundance of the ZIP4 protein at the plasma membrane. Moreover, studies in cultured cells have demonstrated that low micromolar concentrations of zinc stimulate the endocytosis of the mZIP4 protein resulting in a reduction in cellular zinc uptake. In this study, we demonstrate an additional level of hZIP4 regulation involving ubiquitination and degradation of this transporter in elevated zinc concentrations. Mutational analysis identified a cytoplasmic histidine-rich domain that was essential for ubiquitin-dependent degradation of ZIP4 and protection against zinc toxicity. However, this motif was dispensable for zinc-induced endocytosis. These findings indicate that ubiquitin-mediated degradation of the ZIP4 protein is critical for regulating zinc homeostasis in response to the upper tier of physiological zinc concentrations, via a process that is distinct from zinc-stimulated endocytosis.
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Mao
authors.forename: Byung-Eun
authors.initials: BE
authors.lastname: Kim
authors.forename: Fudi
authors.initials: F
authors.lastname: Wang
authors.forename: David J
authors.initials: DJ
authors.lastname: Eide
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Petris
mesh_terms: D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019610:Cytoprotection; D004705:Endocytosis; D006706:Homeostasis; D006801:Humans; D011506:Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D025801:Ubiquitin / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism / Q000633:toxicity*; D000099053:Histidine-Rich Glycoprotein
chemical_list: D027682:Cation Transport Proteins; D011506:Proteins; D012333:RNA, Messenger; C486791:SLC39A4 protein, human; D025801:Ubiquitin; D000099053:Histidine-Rich Glycoprotein; D015032:Zinc