Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets
Because protonation affects the properties of almost all molecules in cells, cytosolic pH (pHc) is usually assumed to be constant. In the model organism yeast, however, pHc changes in response to the presence of nutrients and varies during growth. Since small changes in pHc can lead to major changes in metabolism, signal transduction, and phenotype, we decided to analyze pHc control. Introducing a pH-sensitive reporter protein into the yeast deletion collection allowed quantitative genome-wide analysis of pHc in live, growing yeast cultures. pHc is robust towards gene deletion; no single gene mutation led to a pHc of more than 0.3 units lower than that of wild type. Correct pHc control required not only vacuolar proton pumps, but also strongly relied on mitochondrial function. Additionally, we identified a striking relationship between pHc and growth rate. Careful dissection of cause and consequence revealed that pHc quantitatively controls growth rate. Detailed analysis of the genetic basis of this control revealed that the adequate signaling of pHc depended on inositol polyphosphates, a set of relatively unknown signaling molecules with exquisitely pH sensitive properties. While pHc is a very dynamic parameter in the normal life of yeast, genetically it is a tightly controlled cellular parameter. The coupling of pHc to growth rate is even more robust to genetic alteration. Changes in pHc control cell division rate in yeast, possibly as a signal. Such a signaling role of pHc is probable, and may be central in development and tumorigenesis.