Zinc transporters and their functional integration in mammalian cells

Abstract

Zinc is a ubiquitous biological metal in all living organisms. The spatiotemporal zinc dynamics in cells provide crucial cellular signaling opportunities, but also challenges for intracellular zinc homeostasis with broad disease implications. Zinc transporters play a central role in regulating cellular zinc balance and subcellular zinc distributions. The discoveries of two complementary families of mammalian zinc transporters (ZnTs and ZIPs) in the mid-1990s spurred much speculation on their metal selectivity and cellular functions. After two decades of research, we have arrived at a biochemical description of zinc transport. However, in vitro functions are fundamentally different from those in living cells, where mammalian zinc transporters are directed to specific subcellular locations, engaged in dedicated macromolecular machineries, and connected with diverse cellular processes. Hence, the molecular functions of individual zinc transporters are reshaped and deeply integrated in cells to promote the utilization of zinc chemistry to perform enzymatic reactions, tune cellular responsiveness to pathophysiologic signals, and safeguard cellular homeostasis. At present, the underlying mechanisms driving the functional integration of mammalian zinc transporters are largely unknown. This knowledge gap has motivated a shift of the research focus from in vitro studies of purified zinc transporters to in cell studies of mammalian zinc transporters in the context of their subcellular locations and protein interactions. In this review, we will outline how knowledge of zinc transporters has been accumulated from in-test-tube to in-cell studies, highlighting new insights and paradigm shifts in our understanding of the molecular and cellular basis of mammalian zinc transporter functions.

Zinc in Dog Nutrition, Health and Disease: A Review

“…Figure 1 illustrates zinc metabolism, briefly described in the following subsections. A detailed description of zinc homeostasis in mammals can be found elsewhere [17,23,24].…”

Zinc Signaling in the Mammary Gland: For Better and for Worse

“…Yet, “free” Zn 2+ ions do occur, and are typically sequestered in cellular vesicles and in organelles, including the Golgi, endoplasmic reticulum, and mitochondria, thereby serving as Zn 2+ reservoirs [ 34 , 35 , 36 ]. Regulation of free Zn 2+ in the cytosol is largely achieved either by binding to metallothioneins (MT) or by Zn 2+ transporters [ 27 , 37 , 38 ]. Two protein families are known to mediate Zn 2+ transport across cellular membranes, as Zrt- and Irt-related proteins (ZIP) mediate influx into the cytoplasm and Zn 2+ transporters (ZnT) move Zn 2+ out of the cytoplasm [ 37 , 39 ].…”

“…Regulation of free Zn 2+ in the cytosol is largely achieved either by binding to metallothioneins (MT) or by Zn 2+ transporters [ 27 , 37 , 38 ]. Two protein families are known to mediate Zn 2+ transport across cellular membranes, as Zrt- and Irt-related proteins (ZIP) mediate influx into the cytoplasm and Zn 2+ transporters (ZnT) move Zn 2+ out of the cytoplasm [ 37 , 39 ]. Zn 2+ homeostasis is tightly regulated by these proteins under normal circumstances.…”

“…In addition, activation of the signal transducers and activators of transcription 3, STAT3 pathway functionally modulates Zn 2+ transporter activity [ 27 , 43 ]. Late Zn 2+ signaling events, occurring several hours after cell stimulation, and are dependent upon changes in expression of Zn 2+ transporters that modulate the transfer of Zn 2+ from one compartment to another [ 27 , 37 ]. Both fast and late types of cytoplasmic Zn 2+ rises place this ion in the category of classical second messenger, directly regulating major signaling pathways.…”

The Evolving Role for Zinc and Zinc Transporters in Cadmium Tolerance and Urothelial Cancer

“…Because metals cannot be synthesized nor degraded by the body, they must be acquired from the diet. To assimilate Zn from the diet, transporter systems and pathways specific to Zn have evolved [20] together with mechanisms to store and maintain the homeostasis of Zn in cells and to safeguard against deficiency or toxicity from excessively high Zn intake [21,22].…”