Regulatory Dynamics of Sch9 in Response to Cytosolic Acidification: From Spatial Reconfiguration to Cellular Adaptation to Stresses

Abstract

The regulation of cellular metabolism in response to intracellular and extracellular conditions is critical for cell survival. In Saccharomyces cerevisiae, Sch9 is a well-established substrate of the target of rapamycin complex 1 (TORC1) and regulates metabolic pathways and stress responses. Sch9 is enriched on the vacuolar membrane through binding to PI(3,5)P2, and this localization is essential for TORC1-dependent phosphorylation. Previous studies have demonstrated that glucose starvation and oxidative stress cause the dissociation of Sch9 from the vacuolar membrane. However, the underlying mechanism and physiological significance of the change in Sch9 localization still require elucidation. In this study, we demonstrated that cytosolic pH is a regulator of Sch9 localization. We observed that multiple stress conditions that induce cytosolic acidification consistently led to the detachment of Sch9 from the vacuolar membrane. Furthermore, we confirmed that the affinity between Sch9 and PI(3,5)P2 is pH-dependent in vitro. This pH-dependent localization switch of Sch9 is linked to selective regulation of the TORC1-Sch9 pathway. Impairment of the dissociation of Sch9 from the vacuolar membrane in response to cytosolic acidification resulted in deficient induction of the expression of the stress response gene and delayed the adaptive response to acetic acid stress. These findings indicate that the appropriate control of Sch9 localization is essential for metabolic reprogramming.