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

Wilms, Tobias; Swinnen, Erwin; Eskes, Elja; Dolz‐Edo, Laura; Uwineza, Alice; Essche, Ruben Van; Rosseels, Joëlle; Zabrocki, Piotr; Cameroni, Elisabetta; Franssens, Vanessa; Virgilio, Claudio De; Smits, Gertien J.; Winderickx, Joris

doi:10.1371/journal.pgen.1006835

Cited by 50 publications

(89 citation statements)

References 91 publications

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“…26,27 Deletion of SCH9 results in a marked extension of both CLS and RLS. 16,17,19 While SCH9 deletion causes only a minor increase in basal and starvation-induced autophagic flux, 28 it may affect other downstream aspects of autophagy. For example, Sch9 functions to disassemble the vacuolar proton pump (V-ATPase) upon glucose starvation, and thus its deletion helps maintain vacuolar acidification.…”

Section: Nutrient and Energy Sensors Regulate Cls And Rls In Part Thmentioning

confidence: 99%

“…For example, Sch9 functions to disassemble the vacuolar proton pump (V-ATPase) upon glucose starvation, and thus its deletion helps maintain vacuolar acidification. 28 Maintenance of vacuolar acidification upon SCH9 deletion and its accompanying RLS extension calls to mind the loss of acidification of the vacuole that occurs during aging. 29 The loss of vacuolar acidity observed during normal aging has been shown to contribute to aging via reduced storage of neutral amino acids in the vacuole.…”

Section: Nutrient and Energy Sensors Regulate Cls And Rls In Part Thmentioning

confidence: 99%

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The role of autophagy in the regulation of yeast life span

Tyler

Johnson

2018

Annals of the New York Academy of Sciences

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The goal of the aging field is to develop novel therapeutic interventions that extend human health span and reduce the burden of age-related disease. While organismal aging is a complex, multifactorial process, a popular theory is that cellular aging is a significant contributor to the progressive decline inherent to all multicellular organisms. To explore the molecular determinants that drive cellular aging, as well as how to retard them, researchers have utilized the highly genetically tractable budding yeast Saccharomyces cerevisiae. Indeed, every intervention known to extend both cellular and organismal health span was identified in yeast, underlining the power of this approach. Importantly, a growing body of work has implicated the process of autophagy as playing a critical role in the delay of aging. This review summarizes recent reports that have identified a role for autophagy, or autophagy factors in the extension of yeast life span. These studies demonstrate (1) that yeast remains an invaluable tool for the identification and characterization of conserved mechanisms that promote cellular longevity and are likely to be relevant to humans, and (2) that the process of autophagy has been implicated in nearly all known longevity-promoting manipulations and thus represents an ideal target for interventions aimed at improving human health span.

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Section: Nutrient and Energy Sensors Regulate Cls And Rls In Part Thmentioning

confidence: 99%

Section: Nutrient and Energy Sensors Regulate Cls And Rls In Part Thmentioning

confidence: 99%

The role of autophagy in the regulation of yeast life span

Tyler

Johnson

2018

Annals of the New York Academy of Sciences

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“…The V-ATPase moderates pH fluctuations in the Golgi during a glucose pulse. It is well described that glucose availability influences the cytosolic pH [44][45][46] . Especially, when cells are starved of glucose, the cytosolic pH decreases to a considerably lower value.…”

Section: Resultsmentioning

confidence: 99%

A new pH sensor localized in the Golgi apparatus of Saccharomyces cerevisiae reveals unexpected roles of Vph1p and Stv1p isoforms

Deschamps

Colinet

Zimmermannová

et al. 2020

Sci Rep

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The gradual acidification of the secretory pathway is conserved and extremely important for eukaryotic cells, but until now there was no pH sensor available to monitor the pH of the early Golgi apparatus in Saccharomyces cerevisiae. therefore, we developed a pHluorin-based sensor for in vivo measurements in the lumen of the Golgi. By using this new tool we show that the cis-and medial-Golgi pH is equal to 6.6-6.7 in wild type cells during exponential phase. As expected, V-ATPase inactivation results in a near neutral Golgi pH. We also uncover that surprisingly Vph1p isoform of the V-ATPase is prevalent to Stv1p for Golgi acidification. Additionally, we observe that during changes of the cytosolic pH, the Golgi pH is kept relatively stable, mainly thanks to the V-ATPase. Eventually, this new probe will allow to better understand the mechanisms involved in the acidification and the pH control within the secretory pathway.

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“…Because we found similar phenotypes in vacuolar acidity of the mutant strains with cells purified at five divisions (Figure a), we continued to experiment without purifying cells at a specific age. V‐ATPase activity is essential for vacuole acidification in response to glucose metabolism and is regulated by the assembly of V‐ATPase subunits on the vacuolar membrane (Martinez‐Munoz & Kane, 2008; Wilms et al, 2017). Thus, we examined whether the sir2∆ , tor1∆ , and sir2∆ tor1∆ mutant strains differed in V‐ATPase assembly.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, it has been recently reported that inhibition of TORC1 signaling reduces Pma1 activity almost by half, although detailed mechanisms remain elusive (Deprez, Eskes, Wilms, Ludovico, & Winderickx, 2018). However, the role of TORC1 in Pma1 activity regulation does not seem to be affected by N sources or amino acids, because addition of various amino acids does not alter pHc (Dechant et al, 2014; Wilms et al, 2017). Thus, it is likely that regulation of Pma1 expression and activity for pH homeostasis in yeast would be largely dependent on glucose availability.…”

Section: Introductionmentioning

confidence: 99%

TORC1 signaling regulates cytoplasmic pH through Sir2 in yeast

et al. 2020

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Glucose controls the phosphorylation of silent information regulator 2 (Sir2), a NAD+‐dependent protein deacetylase, which regulates the expression of the ATP‐dependent proton pump Pma1 and replicative lifespan (RLS) in yeast. TORC1 signaling, which is a central regulator of cell growth and lifespan, is regulated by glucose as well as nitrogen sources. In this study, we demonstrate that TORC1 signaling controls Sir2 phosphorylation through casein kinase 2 (CK2) to regulate PMA1 expression and cytoplasmic pH (pHc) in yeast. Inhibition of TORC1 signaling by either TOR1 deletion or rapamycin treatment decreased PMA1 expression, pHc, and vacuolar pH, whereas activation of TORC1 signaling by expressing constitutively active GTR1 (GTR1Q65L) resulted in the opposite phenotypes. Deletion of SIR2 or expression of a phospho‐mutant form of SIR2 increased PMA1 expression, pHc, and vacuolar pH in the tor1Δ mutant, suggesting a functional interaction between Sir2 and TORC1 signaling. Furthermore, deletion of TOR1 or KNS1 encoding a LAMMER kinase decreased the phosphorylation level of Sir2, suggesting that TORC1 signaling controls Sir2 phosphorylation. It was also found that Sit4, a protein phosphatase 2A (PP2A)‐like phosphatase, and Kns1 are required for TORC1 signaling to regulate PMA1 expression and that TORC1 signaling and the cyclic AMP (cAMP)/protein kinase A (PKA) pathway converge on CK2 to regulate PMA1 expression through Sir2. Taken together, these findings suggest that TORC1 signaling regulates PMA1 expression and pHc through the CK2–Sir2 axis, which is also controlled by cAMP/PKA signaling in yeast.

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

Cited by 50 publications

References 91 publications

The role of autophagy in the regulation of yeast life span

The role of autophagy in the regulation of yeast life span

A new pH sensor localized in the Golgi apparatus of Saccharomyces cerevisiae reveals unexpected roles of Vph1p and Stv1p isoforms

TORC1 signaling regulates cytoplasmic pH through Sir2 in yeast

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