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Supplement: 11th International Symposium on Trace Elements in Man and Animals

Multiple Regulatory Mechanisms Maintain Zinc Homeostasis in Saccharomyces cerevisiae ¹

Department of Nutritional Sciences, University of Missouri-Columbia, Columbia, MO 65211

² To whom correspondence should be addressed. E-mail: eided{at}missouri.edu.

	ABSTRACT

TOP ABSTRACT LITERATURE CITED

 
Zinc is an essential nutrient, yet it is toxic if it accumulates in excess amounts within cells; therefore the intracellular labile zinc content of cells is tightly controlled. In Saccharomyces cerevisiae, zinc homeostasis is regulated by the controlled activity of zinc uptake transporters in the plasma membrane and transporters responsible for intracellular zinc compartmentalization. The activity of these transporters is regulated at both transcriptional and posttranscriptional levels in response to zinc. These different mechanisms work together to precisely balance zinc uptake and its storage and utilization.

KEY WORDS: • zinc • yeast • Saccharomyces • regulation • homeostasis

Zinc is an essential catalytic component of > 300 enzymes and a critical component of structural motifs such as zinc fingers. Zinc is estimated to be required for the function of > 3% of the yeast proteome (1), and therefore cells must possess mechanisms to obtain sufficient quantities of this important nutrient. Although zinc is not redox active under physiological conditions, excess zinc can be toxic to cells. Zinc toxicity may be mediated via binding of the cation to inappropriate sites in proteins or cofactors. For example, excess zinc can interfere with mitochondrial aconitase activity and thereby impair respiration (2). The essential but potentially toxic nature of zinc necessitates precise homeostatic control mechanisms. In Escherichia coli, zinc homeostasis is accomplished largely through the transcriptional control of zinc uptake and efflux transporters (3, 4). Recent studies of the regulatory zinc sensors that control expression of these transporters suggest that E. coli cells strive to maintain essentially no labile zinc in their cytoplasm under steady-state growth conditions (5). Similarly, in eukaryotic cells, labile zinc levels are estimated to be at or below the low-nanomolar range under steady-state conditions (6).

Much of our understanding of zinc transport and its regulation in eukaryotes comes from studies of the yeast Saccharomyces cerevisiae. Zinc uptake in S. cerevisiae is time, temperature and concentration dependent and saturable (7– 9). Kinetic studies of zinc uptake by cells grown with different amounts of zinc in the medium suggested the presence of at least two uptake systems. One system has a high affinity for zinc with an apparent K_m of 1 µmol of Zn²⁺/L and is active in zinc-limited cells (10). The second system has a lower affinity for zinc (apparent K_m of 10 µmol of Zn²⁺/L), and its activity is detectable in zinc-replete cells (11). These apparent K_m values are overestimates of the true K_m values, because they don't consider the chelation properties of the uptake assay media. Equilibrium calculations suggest that the actual K_m values are 10 and 100 nmol/L for the high- and low-affinity uptake systems, respectively. Both high- and low-affinity uptake systems are specific for zinc and probably don't contribute to the accumulation of other nutrient metals (11).

The ZRT1 and ZRT2 genes encode the transporter proteins of the high- and low-affinity systems, respectively (10, 11). Proteins Zrt1 and Zrt2 are closely related to one another in that they share 44% amino acid–sequence identity and 67% similarity. Both are members of the zinc (Zn²⁺)-iron (Fe²⁺)-permease (ZIP) ³ family of metal ion transporters. A zrt1 zrt2 mutant is viable (11), which suggests that additional zinc uptake systems are also present in this yeast. We recently determined that one of these additional systems is the Fet4 transporter, which is also responsible for iron and copper uptake (12– 14). The activity of these transporters is tightly regulated to maintain proper zinc homeostasis.

Transcriptional control of zinc uptake in yeast

Zinc uptake in S. cerevisiae is controlled at the transcriptional level in response to intracellular zinc levels. The high-affinity system is induced > 30-fold in zinc-limited cells as a result of increased transcription of the ZRT1 gene (10). The low-affinity system is also regulated through the control of ZRT2 transcription (15). Regulation of these genes in response to zinc is mediated by the product of the ZAP1 gene (15). ZAP1 encodes a transcriptional activator with seven carboxy-terminal C₂H₂ zinc-finger domains and two amino-terminal activation domains. Zap1 was also found to regulate its own transcription through a positive autoregulatory mechanism. This type of regulatory circuitry would allow for an amplified response to changes in zinc levels and Zap1 activity under progressively zinc-limiting conditions.

Zap1 binds to zinc-responsive elements (ZRE) in the promoters of the ZRT1, ZRT2, FET4 and ZAP1 genes and > 40 other genes in the yeast genome (16, 17). A ZRE consensus sequence, 5'-ACCYYNAAGGT-3', was identified and found to be both necessary and sufficient for zinc-responsive transcriptional regulation. Although each gene has one or more consensus ZRE in its promoter, there is differential zinc responsiveness among Zap1 target genes. For example, significantly more zinc is required to repress Zap1-dependent expression of the ZRT2 promoter than is required to repress either the ZRT1 or ZAP1 promoters. These data suggest that Zap1 activity on the ZRT2 promoter may be altered by accessory factors (e.g., other transcription factors) that modulate the response of Zap1 to zinc on this promoter. If zinc controls the affinity of Zap1 for its ZRE binding sites, one possible model is that other proteins bind to the ZRT2 promoter and help stabilize binding of Zap1 to the ZRE and thus increase the affinity of Zap1 for these sites.

The differential sensitivity of the ZRT1, ZRT2 and ZAP1 promoters to zinc is also consistent with the different functions of these proteins and suggests the following scenario: basal (i.e., Zap1-independent) expression of the Zrt2 low-affinity transporter is sufficient to supply zinc to cells under zinc-replete conditions (15). As cells enter the initial phases of zinc limitation, their first response is to increase the activity of the Zrt2 transporter. As zinc limitation becomes more severe, the Zrt1 transporter is induced to provide high-affinity uptake activity for zinc acquisition. Finally, increased expression of the ZAP1 gene, which allows for maximum expression of its target genes, would only be needed under conditions of extreme zinc limitation. Another intriguing question that remains to be answered is precisely how zinc regulates Zap1 activity. Ongoing studies are directed at answering this question.

Posttranslational control of zinc uptake in yeast

A second mechanism in S. cerevisiae regulates zinc transporter activity at a posttranslational level. In zinc-limited cells, Zrt1 is a stable plasma membrane protein. Exposure to high levels of extracellular zinc triggers a rapid loss of Zrt1 uptake activity and protein. This inactivation occurs through zinc-induced endocytosis of the protein and its subsequent degradation in the vacuole (18). Mutations that inhibit the internalization step of endocytosis also inhibit zinc-induced Zrt1 inactivation, and the major vacuolar proteases are required to degrade Zrt1 in response to zinc. Furthermore, immunofluorescence microscopy shows that Zrt1 is in the plasma membrane of zinc-limited cells and is transferred to the vacuole via an endosomelike compartment upon exposure to zinc. Zrt1 inactivation is a relatively specific response to zinc; Cd²⁺ and Co²⁺ trigger the response but do so less effectively than zinc. Excess zinc does not alter the stability of several other plasma membrane proteins. Therefore, zinc-induced Zrt1 inactivation is a specific regulatory mechanism to shut off zinc uptake activity in cells exposed to high extracellular zinc levels and thereby prevent the overaccumulation of this potentially toxic metal.

The mechanism of zinc-induced endocytosis raises a number of exciting new questions. First, although it is clear that zinc induces endocytosis of Zrt1, it is unknown whether this response is induced by a mechanism that senses intracellular or extracellular metal ion levels. Our recent studies suggest that intracellular zinc is the signal. Second, it is unclear whether the signal being monitored represents Zn²⁺ ions per se, the activity of a zinc-dependent or zinc-inhibited enzyme or a more-indirect consequence of high metal accumulation. The observation that Co²⁺ and Cd²⁺ also induce endocytosis of Zrt1 (18) is potentially instructive. Both Co²⁺ and Cd²⁺ have similar coordination chemistries to Zn²⁺ and bind to protein ligands in a similar fashion. Therefore, the simplest hypothesis is that Zn²⁺ ions trigger endocytosis directly and that Co²⁺ and Cd²⁺ mimic that signal. The lower activity of Co²⁺ and Cd²⁺ in triggering the response may be due to a greater specificity of the sensing mechanism for Zn²⁺ or different uptake efficiencies for different metal ions. A third unanswered question regards how the zinc signal is transmitted to Zrt1. This could occur by the metal binding directly to the transporter or via an indirect signal transduction pathway. Recent studies demonstrate that Zrt1 is ubiquitinated before endocytosis, which suggests that this modification serves as a signal for recruitment of the protein into clathrin-coated pits (19). A similar role for ubiquitin was also found for other S. cerevisiae and some mammalian plasma membrane proteins (20). Zinc-induced ubiquitination of Zrt1 occurs on the lysine residue K195, which is located in a cytosolic loop region of the protein. Therefore, the principal question currently is, How does zinc control ubiquitination of Zrt1?

The posttranslational regulatory system is clearly separate from the transcriptional control system given that inactivation of Zrt1 activity occurs normally in a zap1-deletion mutant (18). However, these two systems undoubtedly work together to maintain the homeostatic control of intracellular zinc levels. It is interesting to note that the transcriptional control system exerts its greatest effect on ZRT1 expression when cell-associated zinc levels vary between 0.01 and 0.07 nmol of Zn/1 million cells (i.e., 5–40 million atoms of zinc/cell) (18). Approximately 90% repression of a ZRT1 promoter–lacZ fusion was observed when cell-associated zinc levels rose to 0.07 nmol of zinc/1 million cells (16). In contrast, the posttranslational response is triggered only at cell-associated zinc levels of > 0.07 nmol of Zn/1 million cells. Thus, we envision a two-tiered regulatory system in which the transcriptional control responds to moderate changes in zinc availability and the posttranslational control responds to more extreme zinc excess. A likely scenario in which the posttranslational control would be important for maintaining zinc homeostasis is when zinc-limited cells are suddenly exposed to high levels of zinc, a condition we refer to as "zinc shock." The rapid downregulation of zinc uptake by Zrt1 endocytosis helps to prevent overaccumulation of zinc. This fast response would not be possible solely through the transcriptional control of a stable plasma membrane protein. During inactivation of zinc uptake activity, other systems may be induced to facilitate storage of the excess zinc or mediate its efflux from the cell.

Intracellular zinc transport in yeast

Once zinc is taken up across the plasma membrane, some of the metal must be transported into organelles (such as the mitochondria) and compartments of the secretory system to serve as a cofactor of the zinc-dependent proteins that are found within those compartments. Furthermore, the vacuole is implicated in the storage and detoxification of zinc (21). Very little is known about the specific transporters involved in intracellular zinc trafficking. Three potential intracellular zinc transporters have been identified in S. cerevisiae. These transporters are three members of the cation diffusion facilitator (CDF) family: Zrc1, Cot1 and Msc2. ZRC1 was isolated as a determinant of zinc resistance; i.e., overexpression of ZRC1 results in increased ability of these cells to tolerate high zinc levels (22). A zrc1 mutation was later found to increase sensitivity to lipid hydroperoxides and decrease glutathione levels by 40% (23). The relationship between these phenotypes and zinc, if any, is unknown. The COT1 gene was isolated in a similar fashion to ZRC1, i.e., as a suppressor of cobalt toxicity, but was later found to confer zinc resistance as well (24, 25). Disruption of either ZRC1 or COT1 resulted in greater sensitivity to excess zinc, which further supports the role of these genes in zinc compartmentalization.

Zrc1 and Cot1 are closely related proteins (60% identity) with 400 amino acids and 6 potential transmembrane domains. The physiological roles of these transporters remain unclear. Neither ZRC1 nor COT1 are essential genes, and a zrc1 cot1 mutant is also viable. Thus, these two genes do not together provide a function essential for growth. Neither protein appears to catalyze zinc efflux from the cell. Although Cot1 was originally proposed to be a mitochondrial protein (25), the subcellular location of both Zrc1 and Cot1 has recently been identified as the vacuole (26). This localization was determined with overexpressed proteins and so must be viewed with caution. However, with this caveat aside, these results suggest that these transporters are responsible for zinc sequestration into the vacuole (26). Because zinc transport into the vacuole has been attributed to a Zn²⁺/H⁺ antiport system (27, 28), this leads to the conclusion that this is the transport mechanism used by Zrc1 and Cot1. This mechanism would then provide a simple explanation for the zinc sensitivity observed in vacuolar H⁺-ATPase mutants (29, 21); i.e., mutants defective for vacuolar acidification lack the H⁺ gradient that is necessary to drive zinc sequestration.

Surprisingly, transcription of ZRC1 is induced in zinc-limited cells by Zap1. This induction is paradoxical given the role of Zrc1 in zinc detoxification. We have shown that this increase in ZRC1 expression is a novel "proactive" mechanism of zinc homeostasis and stress tolerance. Zinc-limited cells express high levels of the plasma membrane zinc uptake transporters. Zrc1 and its induction by Zap1 are critical components of the ability of the cell to tolerate zinc shock by transporting excess cytosolic zinc into the vacuole. We propose that proactive homeostatic regulation such as we documented for ZRC1 may be a common but largely unrecognized phenomenon.

We also identified a gene in yeast, ZRT3, that plays a role in vacuolar zinc transport (30). Although distantly related to Zrt1 and Zrt2, Zrt3 is a potential transport protein that is a member of the ZIP family. Like the ZRT1 and ZRT2 genes, ZRT3 is a ZAP1 target gene and is upregulated in zinc-limited cells. Our analysis of Zrc1, Cot1 and Zrt3 has generated this scenario of zinc storage in yeast: zinc-replete wild-type cells generate a vacuolar zinc storage pool through the action of the Zrc1 and Cot1 transporters. This pool of stored zinc is in a labile form that can be mobilized when cells are deprived of extracellular zinc. Mobilization of the vacuolar store is the role of Zrt3, whose expression is induced under zinc-limiting conditions. Several aspects of this model have already been confirmed (30).

Finally, a third member of the CDF family was recently implicated in zinc transport in S. cerevisiae. This transporter is encoded by the MSC2 gene. Although Msc2 is a member of the CDF family, it differs from most other members by having 12 rather than 6 transmembrane domains and 2 rather than 1 histidine-rich region. Paradoxically, MSC2 was first identified by a transposon insertion allele that caused an increased frequency of meiotic sister chromatid recombination events (31). This effect was found to be allele specific and did not occur when the MSC2 gene was deleted. The connection between MSC2 and recombination is still a mystery, but a subsequent analysis suggests a role of Msc2 in zinc transport (32). An msc2 deletion mutation caused decreased viability on respired carbon sources and an abnormal cellular morphology when cells were grown at an elevated temperature. Both of these phenotypes were suppressible by zinc supplementation, which suggests some defect in zinc metabolism in this strain. The msc2 mutant also had alterations in intracellular zinc content and an apparent increase in the regulatory zinc pool sensed by Zap1. The Msc2 protein was localized to the nuclear envelope. An attractive hypothesis is that Msc2 mediates zinc transport into the intermembrane space of this compartment. This intriguing model awaits further testing.

In summary, yeasts maintain zinc homeostasis through the regulated activity of transporter proteins that are found in the plasma membrane and the membranes of intracellular compartments. This regulation is mediated at both transcriptional and posttranslational levels and occurs in response to changes in intracellular zinc levels. Although it remains to be tested, it is our hypothesis that these mechanisms maintain intracellular zinc at extremely low levels as are found in bacteria and plants.

	FOOTNOTES

 
¹ Published in a supplement to The Journal of Nutrition. Presented as part of the 11th meeting of the international organization, "Trace Elements in Man and Animals (TEMA)," in Berkeley, California, June 2–6, 2002. This meeting was supported by grants from the National Institutes of Health and the U.S. Department of Agriculture and by donations from Akzo Nobel Chemicals, Singapore; California Dried Plum Board, California; Cattlemen's Beef Board and National Cattlemen's Beef Association, Colorado; GlaxoSmithKline, New Jersey; International Atomic Energy Agency, Austria; International Copper Association, New York; International Life Sciences Institute Research Foundation, Washington, D.C.; International Zinc Association, Belgium; Mead Johnson Nutritionals, Indiana; Minute Maid Company, Texas; Perrier Vittel Water Institute, France; U.S. Borax, Inc., California; USDA/ARS Western Human Nutrition Research Center, California and Wyeth-Ayerst Global Pharmaceuticals, Pennsylvania. Guest editors for the supplement publication were Janet C. King, USDA/ARS WHNRC and the University of California at Davis; Lindsay H. Allen, University of California at Davis; James R. Coughlin, Coughlin & Associates, Newport Coast, California; K. Michael Hambidge, University of Colorado, Denver; Carl L. Keen, University of California at Davis; Bo L. Lönnerdal, University of California at Davis and Robert B. Rucker, University of California at Davis.

³ Abbreviations used: CDF, cation diffusion facilitator; ZIP, zinc-iron permease; ZRE, zinc-responsive element.

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