Abstract
The conserved protein kinase Sch9 is a central player in the nutrient-induced signaling network in yeast, although only few of its direct substrates are known. We now provide evidence that Sch9 controls the vacuolar proton pump (V-ATPase) to maintain cellular pH homeostasis and ageing. A synthetic sick phenotype arises when deletion of SCH9 is combined with a dysfunctional V-ATPase, and the lack of Sch9 has a significant impact on cytosolic pH (pHc) homeostasis. Sch9 physically interacts with, and influences glucose-dependent assembly/disassembly of the V-ATPase, thereby integrating input from TORC1. Moreover, we show that the role of Sch9 in regulating ageing is tightly connected with V-ATPase activity and vacuolar acidity. As both Sch9 and the V-ATPase are highly conserved in higher eukaryotes, it will be interesting to further clarify their cooperative action on the cellular processes that influence growth and ageing.
Highlights
In Saccharomyces cerevisiae, Sch9 is part of the highly conserved TORC1 pathway which plays a central role in the nutrient-induced signaling network, thereby affecting many aspects of yeast physiology such as stress resistance, longevity and cell growth [1,2,3]
We identified multiple components of the highly conserved vacuolar proton pump (V-ATPase) which mediates the luminal acidification of multiple biosynthetic and endocytic organelles
We found Sch9 physically interacts with the V-ATPase to regulate its assembly state in response to glucose availability and TORC1 activity
Summary
In Saccharomyces cerevisiae, Sch is part of the highly conserved TORC1 pathway which plays a central role in the nutrient-induced signaling network, thereby affecting many aspects of yeast physiology such as stress resistance, longevity and cell growth [1,2,3]. It has been proposed that Snf, the orthologue of mammalian AMP kinase, modulates Sch activity by phosphorylation [10]. As three different kinases modulate Sch activity in response to diverse stimuli, Sch appears to act as a major integrator that regulates various aspects of yeast physiology. A prime example of this is the control of lifespan by Sch. A prime example of this is the control of lifespan by Sch9 Both tor1Δ and sch9Δ strains display increased lifespan as compared to the WT strain [2, 11], and downregulation of nutrient signaling via the TORC1-Sch branch seems to be part of an evolutionary conserved mechanism that extends lifespan across a wide range of eukaryotic species [12, 13]
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