The yeast protein kinase Sch9 adjusts V-ATPase assembly/disassembly to control pH homeostasis and longevity in response to glucose availability

The evolutionary conserved TOR complex 1 controls growth in response to the quality and quantity of nutrients such as carbon and amino acids. The protein kinase Sch9 is the main TORC1 effector in yeast. However, only few of its direct targets are known. In this study, we performed a genome-wide screening looking for mutants which require Sch9 function for their survival and growth. In this way, we identified multiple components of the highly conserved vacuolar proton pump (V-ATPase) which mediates the luminal acidification of multiple biosynthetic and endocytic organelles. Besides a genetic interaction, we found Sch9 also physically interacts with the V- ATPase to regulate its assembly state in response to glucose availability and TORC1 activity. Moreover, the interaction with the V-ATPase has consequences for ageing as it allowed Sch9 to control vacuolar pH and thereby trigger either lifespan extension or lifespan shortening. Hence, our results provide insights into the signaling mechanism coupling glucose availability, TORC1 signaling, pH homeostasis and longevity. As both Sch9 and the V-ATPase are highly conserved and implicated in various pathologies, these results offer fertile ground for further research in higher eukaryotes

Prior Information Properties.

<p>Prior Information Properties.</p

Behaviour of MSE and MSSRE with respect to changes in the connection strengths differing between the competing networks.

<p>The change in MSE (Panel A) and MSSRE (Panel B) in simulations with MN3% and MN5% relative to the simulations with CN are shown in the y-axis. In the x-axis, the total magnitude of the missing connections which existed in CN but had been ignored in the imposed network structure are plotted.</p

Values of Connection Strengths in .

<p>In this plot, each black point represents the connection strength of an element in the unrestricted connectivity matrix which was restricted to 0 previously in the imposed network structure. Each column represents one transcription factor. Red stars are the connections which were missing in the imposed network structure whereas in CN these elements have nonzero values indicating existing connections instead. The outlier elements for each transcription factor identified at a whisker length of 2 are surrounded with additional squares in blue.</p

Discrimination Performance.

<p>Discrimination Performance.</p