Genome-wide analysis of intracellular pH reveals quantitative control of cell division rate by pHc in Saccharomyces cerevisiae

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