Abstract
The mouse mZip1 and mZip3 zinc transporters have been implicated in zinc acquisition by the cells of many tissues. This hypothesis raised the question of whether activity of these proteins is regulated to maintain zinc homeostasis. Neither mZIP1 nor mZIP3 mRNA levels are highly regulated by zinc status. Therefore, we investigated whether zinc controls the activity of these proteins post-translationally by altering their subcellular distribution. When expressed in transfected cells grown in zinc-replete medium, both mZip1 and mZip3 were largely present in intracellular organelles. However, these proteins were found to rapidly transit between the plasma membrane and intracellular compartments in zinc-replete cells. Zinc deficiency increased plasma membrane levels of mZip1 and mZip3 by decreasing their rates of endocytosis. Greater zinc deficiency was required to alter mZip3 distribution than was needed to affect mZip1. Increased surface levels correlated with increased zinc uptake activity. Taken together, these results suggest that post-translational control of mZip1 and mZip3 localization plays a role in zinc homeostasis. Moreover, our results indicate that zinc-responsive endocytosis is a conserved mechanism controlling activity of many mammalian zinc uptake transporters.
Highlights
Zinc is an essential nutrient because of the many important roles it plays in biology
Expression and Subcellular Distribution of mZip1-HA and mZip3-HA Proteins in Transfected HEK293 Cells—Previous studies established that the mouse Zip1 and Zip3 proteins stimulate zinc uptake when expressed at high levels in transiently transfected HEK293 cells
Regulating zinc uptake transporter activity is an important aspect of zinc homeostasis in bacteria, yeast, and plants and its relevance to mammalian zinc metabolism is becoming increasingly clear
Summary
Zinc is an essential nutrient because of the many important roles it plays in biology. Human and mouse Zip proteins have been shown to be active for zinc uptake and specific for zinc as their substrate [17,18,19]. ZIP3 is widely expressed in many tissue types (Unigene EST data base) it is most abundant in testes [19] These results suggest that Zip and Zip are involved in zinc acquisition by many cells of the body. Regulation of ZIP protein activity has been found to occur at both transcriptional and post-translational levels. When zinc is resupplied to zinc-deficient cells expressing high levels of Zrt, the transporter is rapidly inactivated [21]. Regulation of some zinc uptake transporters occurs at the level of mRNA abundance possibly via transcriptional control. This paper is available on line at http://www.jbc.org
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