Regulation of cation balance in Saccharomyces cerevisiae

Abstract

All living organisms require nutrient minerals for growth and have developed mechanisms to acquire, utilize, and store nutrient minerals effectively. In the aqueous cellular environment, these elements exist as charged ions that, together with protons and hydroxide ions, facilitate biochemical reactions and establish the electrochemical gradients across membranes that drive cellular processes such as transport and ATP synthesis. Metal ions serve as essential enzyme cofactors and perform both structural and signaling roles within cells. However, because these ions can also be toxic, cells have developed sophisticated homeostatic mechanisms to regulate their levels and avoid toxicity. Studies in Saccharomyces cerevisiae have characterized many of the gene products and processes responsible for acquiring, utilizing, storing, and regulating levels of these ions. Findings in this model organism have often allowed the corresponding machinery in humans to be identified and have provided insights into diseases that result from defects in ion homeostasis. This review summarizes our current understanding of how cation balance is achieved and modulated in baker's yeast. Control of intracellular pH is discussed, as well as uptake, storage, and efflux mechanisms for the alkali metal cations, Na(+) and K(+), the divalent cations, Ca(2+) and Mg(2+), and the trace metal ions, Fe(2+), Zn(2+), Cu(2+), and Mn(2+). Signal transduction pathways that are regulated by pH and Ca(2+) are reviewed, as well as the mechanisms that allow cells to maintain appropriate intracellular cation concentrations when challenged by extreme conditions, i.e., either limited availability or toxic levels in the environment.

Figure 1

During glucose starvation, changes in intracellular pH serve a signaling function. (A) In the presence of glucose, Pma1 and the V-ATPase are active; cytosolic pH is 7.0–7.2 and vacuolar pH is 5.6. PKA is active, and V-ATPase association is proposed to regulate its activity. Inositol synthesis is active due to sequestration of the Opi1 repressor on the surface of the ER. (B) In glucose-starved cells, cytosolic pH drops due to decreased activity of Pma1 and dissociation of the V-ATPase subcomplexes. Opi1 is released from the ER due to protonation of phosphatadic acid (PA); Op1 entry into the nucleus represses expression of INO1 by Ino2/4 transcriptonal activators. Bright colors in A indicate active proteins; dull colors in B indicate reduced activity. See text for details.

Figure 2

The major transporters responsible for uptake, efflux, and intracellular transport of alkali metal ions in S. cerevisiae. Note that the V-ATPase also resides in endosomes and late Golgi, but was omitted from the figure due to space constraints.

Figure 3

Environmental stress induces Ca²⁺ influx into S. cerevisiae via the Mid1/Cch1 high affinity Ca²⁺ channel and activation of the calcineurin phosphatase (CN), which dephosphorylates substrates Crz1, Aly1, Slm1/2, and Hph1. See text for details. Note that the V-ATPase also resides in endosomes and late Golgi, but was omitted from the figure due to space constraints.

Figure 4

Abundance of common elements in S. cerevisiae. Strain BY4741 was grown in rich (YPD) medium and ionic content was measured using inductively coupled plasma-atomic emission spectroscopy. (A) Data expressed as parts per million (ppm). (B) Abundance of metals, with data expressed as parts per billion (ppb). Data from Eide et al. (2005).

Figure 5

Iron homeostasis in S. cerevisiae. Protein products of Aft1- and Aft2-regulated genes are shown in their respective subcellular locations. Red spheres are Fe(III); orange spheres are Fe(II). Ccc1 and mitochondrial proteins involved in the heme synthesis, the TCA cycle, biotin synthesis, and glutamate synthesis are down-regulated by iron deficiency. Reproduced with permission (Philpott and Smith 2013).

Figure 6

Zinc homeostasis. (A) Schematic of Zap1. Regions representing zinc fingers are filled and numbered. Activation domains (AD) in black are embedded within zinc-regulatory domains (ZRD) in orange. Reproduced with permission (Frey and Eide 2011). (B) Transcriptional response to zinc deficiency. Proteins involved in zinc homeostasis are on the left, proteins involved in metabolic adaptation to zinc deficiency on the right. Yellow spheres indicate up-regulation, blue spheres indicate down-regulation, gray spheres indicate no zinc regulation. Subcellular localizations are shown. PM, plasma membrane; MITO, mitochondria; ORF, open reading frame. Reproduced with permission (Eide 2009).

Figure 7

Copper homeostasis. Proteins involved in the regulation, uptake, distribution, and utilization of copper. Subcellular localizations are indicated. Reproduced with permission (Nevitt et al. 2012).

Figure 8

Manganese homeostasis. Proteins involved in the transport and utilization of manganese are shown. Subcellular localization of proteins observed under manganese-deficient conditions is depicted.