Molecular and cell biological studies of mammalian zinc transporters
Metadata[+] Show full item record
[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Zinc is an essential trace element in all organisms. The importance of the hZIP4 human zinc transporter is highlighted by its causative role in a genetic disease of zinc deficiency, acrodermatitis enteropathica (AE). The overall goal of my project is to understand the cellular and molecular mechanisms of hZIP4 post-translational regulation. The abundance of hZIP4 on the plasma membrane is dependent on zinc availability, and hZIP4 undergoes zinc-stimulated endocytosis. More importantly, an additional level of hZIP4 post-translational regulation was identified, which involves ubiquitination and degradation of this protein by elevated zinc treatments. Furthermore, endocytosis is a prerequisite for its degradation requiring both proteasomes and lysosomes. One characteristic feature of many ZIP proteins is the intracellular histidine-rich region between transmembrane domains 3 and 4. The essentiality of the histidine-rich segment for ubiquitin-mediated degradation of hZIP4 was demonstrated. It functions to prevent cell toxicity from zinc overload. Furthermore, a cytosolic lysine residue is solely responsible for hZIP4 ubiquitination. However, mutation of this lysine does not interfere with zinc-stimulated hZIP4 degradation, suggesting the existence of alternative degradation pathways independent of ubiquitination. The implication that hZIP4 has multiple degradation pathways may provide a precise system regulating hZIP4 protein levels to avoid zinc overload, accounting for the essential role of hZIP4 in achieving zinc homeostasis.
Access is limited to the campuses of the University of Missouri.