The trafficking of metal ion transporters of the Zrt- and Irt-like protein family.

Metal ion transporters of the Zrt- and Irt-like protein (ZIP, or SLC39A) family transport zinc, iron, manganese and/or cadmium across cellular membranes and into the cytosol. The 14 human ZIP family proteins are expressed in a wide variety of tissues and function in many different cellular processes. Many of these proteins (including ZIP1, 2, 3, 4, 5, 6/10, 8, 9, 11, 12, 14) are situated, at least some of the time, on the plasma membrane, where they mediate metal ion uptake into cells. Their level on the cell surface can be controlled rapidly via protein trafficking in response to the ions they transport. For example, the cell surface level of many ZIPs (including ZIP1, 3, 4, 8 and 12) is mediated by the available concentration of zinc. Zinc depletion causes a decrease in endocytosis and degradation, resulting in more ZIP on the surface to take up the essential ion. ZIP levels on the cell surface are a balance between endocytosis, recycling and degradation. We review the trafficking mechanisms of human ZIP proteins, highlighting possible targeting motifs and suggesting a model of zinc-mediated endocytic trafficking. We also provide two possible models for ZIP14 trafficking and degradation.