Regulatory dynamics of Sch9 in response to cytosolic acidification: From spatial reconfiguration to cellular adaptation to stresses

The regulation of cellular metabolism is crucial for cell survival, with Sch9 in <i>Saccharomyces cerevisiae</i> serving a key role as a substrate of TORC1. Sch9 localizes to the vacuolar membrane through binding to PI(3,5)P₂, which is necessary for TORC1-dependent phosphorylation. This study demonstrates that cytosolic pH regulates Sch9 localization. Under stress conditions that induce cytosolic acidification, Sch9 detached from the vacuolar membrane. <i>In vitro</i> experiments confirmed that Sch9's affinity for PI(3,5)P₂ is pH-dependent. This pH-dependent localization switch is essential for regulating the TORC1-Sch9 pathway. Impairment of the dissociation of Sch9 from the vacuolar membrane in response to cytosolic acidification resulted in the deficient induction of stress response gene expression and delayed the adaptive response to acetic acid stress. These findings indicate the importance of proper Sch9 localization for metabolic reprogramming and stress response in yeast cells.