Budding Yeast Escape Commitment to the Phosphate Starvation Program Using Gene Expression Noise

Vardi, Noam; Levy, Sagi; Assaf, Michael; Carmi, Miri; Barkai, Naama

doi:10.1016/j.cub.2013.08.043

Cited by 38 publications

(42 citation statements)

References 33 publications

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“…Several studies have implicated enzymes of polyP metabolism in the onset and stabilization of the yeast phosphate starvation program, the PHO pathway (1,7,57). Consistent with this, we found that de-regulation of VTC5 expression alters activation of the PHO pathway.…”

Section: Vtc5 Is a Novel Subunit Of The Polyphosphate Polymerasesupporting

confidence: 89%

Vtc5, a Novel Subunit of the Vacuolar Transporter Chaperone Complex, Regulates Polyphosphate Synthesis and Phosphate Homeostasis in Yeast

Desfougères

Gerasimaitė

Jessen

et al. 2016

Journal of Biological Chemistry

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SPX domains control phosphate homeostasis in eukaryotes.Ten genes in yeast encode SPX-containing proteins, among which YDR089W is the only one of unknown function. Here, we show that YDR089W encodes a novel subunit of the vacuole transporter chaperone (VTC) complex that produces inorganic polyphosphate (polyP). The polyP synthesis transfers inorganic phosphate (P i ) from the cytosol into the acidocalcisome-and lysosome-related vacuoles of yeast, where it can be released again. It was therefore proposed for buffer changes in cytosolic P i concentration (Thomas, M. R., and O'Shea, E. K. (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 9565-9570). Vtc5 physically interacts with the VTC complex and accelerates the accumulation of polyP synthesized by it. Deletion of VTC5 reduces polyP accumulation in vivo and in vitro. Its overexpression hyperactivates polyP production and triggers the phosphate starvation response via the PHO pathway. Because this Vtc5-induced starvation response can be reverted by shutting down polyP synthesis genetically or pharmacologically, we propose that polyP synthesis rather than Vtc5 itself is a regulator of the PHO pathway. Our observations suggest that polyP synthesis not only serves to establish a buffer for transient drops in cytosolic P i levels but that it can actively decrease or increase the steady state of cytosolic P i .Phosphate is a limiting factor for the growth of living organisms. It is mainly taken up by the cells as P i and incorporated in biological molecules, including ATP, nucleic acids, and phospholipids. P i plays a major role in the regulation of biochemical pathways through phosphorylation, pyrophosphorylation, and polyphosphorylation. Its concentration affects the free energy liberated by the hydrolysis of ATP and other nucleoside di-and triphosphates. Therefore, P i homeostasis (import, usage, storage, and export) is regulated (1, 2), and P i can be accumulated and stored as a polymer of P i units called polyphosphate (polyP).3 One mode of regulation operates on the transcriptional level. The PHO pathway, which is a P i -dependent transcriptional program in yeast, has been extensively characterized (2). Transcription of the PHO genes is regulated by the transcription factors Pho4 and Pho2. Phosphorylated Pho2 interacts with Pho4 to induce expression of the PHO genes. Pho2 is a target of Cdc28 kinase in vitro suggesting a coordination between cell cycle progression and nutrient availability (3). Pho4 is itself regulated by the cyclin-dependent kinase Pho85 and its cyclin Pho80. Under P i -rich conditions, the Pho80-Pho85 complex phosphorylates Pho4, thereby restricting the localization of the transcription factor to the cytosol (4, 5). Under P i limitation, Pho80/Pho85 is inhibited, and the nonphosphorylated Pho4 is imported into the nucleus, allowing transcription of PHO genes. Pho80/85 is regulated by the cyclin-dependent kinase inhibitor Pho81. Inhibition of Pho80/85 by Pho81 is facilitated by the inositol pyrophosphate 1-IP 7 , which is produced by Vip1 (6). However,...

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Section: Vtc5 Is a Novel Subunit Of The Polyphosphate Polymerasesupporting

confidence: 89%

Vtc5, a Novel Subunit of the Vacuolar Transporter Chaperone Complex, Regulates Polyphosphate Synthesis and Phosphate Homeostasis in Yeast

Desfougères

Gerasimaitė

Jessen

et al. 2016

Journal of Biological Chemistry

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“…Since cell-to-cell variability in gene expression underlies important phenotypic phenomena such as persistence (Balaban et al 2004), competence (Maamar et al 2007), latency (Dar et al 2014), metastasis (Lee et al 2014), responsiveness to fluctuating environments (Acar et al 2005(Acar et al , 2008Blake et al 2006;Kaufmann et al 2007;Levy et al 2012;Vardi et al 2013), and triggering of meiosis (Nachman et al 2007), our results suggest that the probability and efficiency of these processes will be tightly coupled to environmental conditions, with potential evolutionary implications. Gene expression noise is higher at lower growth rates.…”

mentioning

confidence: 90%

Noise in gene expression is coupled to growth rate

et al. 2015

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Genetically identical cells exposed to the same environment display variability in gene expression (noise), with important consequences for the fidelity of cellular regulation and biological function. Although population average gene expression is tightly coupled to growth rate, the effects of changes in environmental conditions on expression variability are not known. Here, we measure the single-cell expression distributions of approximately 900 Saccharomyces cerevisiae promoters across four environmental conditions using flow cytometry, and find that gene expression noise is tightly coupled to the environment and is generally higher at lower growth rates. Nutrient-poor conditions, which support lower growth rates, display elevated levels of noise for most promoters, regardless of their specific expression values. We present a simple model of noise in expression that results from having an asynchronous population, with cells at different cell-cycle stages, and with different partitioning of the cells between the stages at different growth rates. This model predicts non-monotonic global changes in noise at different growth rates as well as overall higher variability in expression for cell-cycle-regulated genes in all conditions. The consistency between this model and our data, as well as with noise measurements of cells growing in a chemostat at well-defined growth rates, suggests that cell-cycle heterogeneity is a major contributor to gene expression noise. Finally, we identify gene and promoter features that play a role in gene expression noise across conditions. Our results show the existence of growth-related global changes in gene expression noise and suggest their potential phenotypic implications.

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“…Synthesis and degradation of polyP are required to buffer cytosolic P i concentration, and this is essential for cells in order to adapt to changing phosphate availability in the environment. That cells actively regulate cytosolic P i is also underscored by the existence of a dedicated transcriptional program, the phosphate signal transduction (PHO) pathway (Thomas and O'Shea, 2005;Vardi et al, 2013), which responds to cytosolic P i levels. Since polyP metabolism does not only respond to cytosolic P i concentration but can even set it (Desfougeres et al, 2016a), the exploration of polyP synthesis and turnover is crucial for understanding P i metabolism and nutrient signaling in general.…”

Section: Introductionmentioning

confidence: 99%

Ppn2, a novel Zn2+-dependent polyphosphatase in the acidocalcisome-like yeast vacuole

Gerasimaitė

Mayer

2017

Journal of Cell Science

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Acidocalcisome-like organelles are found in all kingdoms of life. Many of their functions, such as the accumulation and storage of metal ions, nitrogen and phosphate, the activation of blood clotting and inflammation, depend on the controlled synthesis and turnover of polyphosphate ( polyP), a polymer of inorganic phosphate linked by phosphoric anhydride bonds. The exploration of the role of acidocalcisomes in metabolism and physiology requires the manipulation of polyP turnover, yet the complete set of proteins responsible for this turnover is unknown. Here, we identify a novel type of polyphosphatase operating in the acidocalcisome-like vacuoles of the yeast Saccharomyces cerevisiae, which we called Ppn2. Ppn2 belongs to the PPP-superfamily of metallophosphatases, is activated by Zn 2+ ions and exclusively shows endopolyphosphatase activity. It is sorted to vacuoles via the multivesicular body pathway. Together with Ppn1, Ppn2 is responsible for a substantial fraction of polyphosphatase activity that is necessary to mobilize polyP stores, for example in response to phosphate scarcity. This finding opens the way to manipulating polyP metabolism more profoundly and deciphering its roles in phosphate and energy homeostasis, as well as in signaling.

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Budding Yeast Escape Commitment to the Phosphate Starvation Program Using Gene Expression Noise

Cited by 38 publications

References 33 publications

Vtc5, a Novel Subunit of the Vacuolar Transporter Chaperone Complex, Regulates Polyphosphate Synthesis and Phosphate Homeostasis in Yeast

Vtc5, a Novel Subunit of the Vacuolar Transporter Chaperone Complex, Regulates Polyphosphate Synthesis and Phosphate Homeostasis in Yeast

Noise in gene expression is coupled to growth rate

Ppn2, a novel Zn2+-dependent polyphosphatase in the acidocalcisome-like yeast vacuole

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