Valproate activates the Snf1 kinase in Saccharomyces cerevisiae by decreasing the cytosolic pH

Salsaa, Michael; Aziz, Kerestin; Lazcano, Pablo; Schmidtke, Michael W.; Tarsio, Maureen; Hüttemann, Maik; Reynolds, Christian A.; Kane, Patricia M.; Greenberg, Miriam L.

doi:10.1016/j.jbc.2021.101110

Cited by 7 publications

(10 citation statements)

References 84 publications

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“…The inositol-depleting mood stabilizing drugs lithium and VPA have been shown to activate AMPK (Avery and Bumpus, 2014; Bao et al, 2019; Salsaa et al, 2021). To test the prediction that activation of AMPK by mood stabilizers induces nuclear localization of IP6K1, cells were treated with VPA (1 mM) or lithium (10 mM) for 24 h, and phosphorylated (active) AMPK was measured by Western blot (Willows et al, 2017).…”

Section: Resultsmentioning

confidence: 99%

“…As a master metabolic regulator, canonical activation of AMPK is mediated by an increase in the AMP/ADP:ATP ratio (Garcia and Shaw, 2017). Interestingly, the inositol-depleting drugs VPA and lithium have been shown to activate AMPK in multiple cell types, and VPA was shown to activate the AMPK homolog Snf1 in yeast (Avery and Bumpus, 2014; Bao et al, 2019; Lee et al, 2020; Salsaa et al, 2021). Furthermore, a recent study identified inositol as a direct allosteric inhibitor of AMPK that acts by blocking activation by AMP (Hsu et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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Phosphatidic acid inhibits inositol synthesis by inducing nuclear translocation of IP6K1 and repression of myo-inositol-3-P synthase

Lazcano

Schmidtke

Onu

et al. 2022

Preprint

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Inositol is an essential metabolite that serves as a precursor for structural and signaling molecules. Although perturbation of inositol homeostasis has been implicated in numerous human disorders, surprisingly little is known about how inositol levels are regulated in mammalian cells. A recent study in mouse embryonic fibroblasts (MEFs) demonstrated that nuclear translocation of inositol hexakisphosphate kinase 1 (IP6K1) mediates repression of myo-3-P synthase (MIPS), the rate-limiting inositol biosynthetic enzyme. Binding of IP6K1 to phosphatidic acid (PA) is required for this repression. The current study was carried out to elucidate the role of PA in IP6K1 repression. The results indicate that increasing PA levels through pharmacological stimulation of phospholipase D (PLD) or direct supplementation of 18:1 PA induces nuclear translocation of IP6K1 and represses expression of MIPS protein. This effect was specific to PA synthesized in the plasma membrane, as ER-derived PA did not induce IP6K1 translocation. PLD-mediated PA synthesis can be stimulated by the master metabolic regulator 5' AMP-activated protein kinase (AMPK). Activation of AMPK by glucose deprivation or by treatment with the mood stabilizing drugs valproate (VPA) or lithium recapitulated IP6K1 nuclear translocation and decreased MIPS expression. This study demonstrates for the first time that modulation of PA levels through the AMPK-PLD pathway regulates IP6K1-mediated repression of MIPS.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phosphatidic acid inhibits inositol synthesis by inducing nuclear translocation of IP6K1 and repression of myo-inositol-3-P synthase

Lazcano

Schmidtke

Onu

et al. 2022

Preprint

Self Cite

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“…Increased glycolytic flux beyond glucose-6-phosphate increases Vma1 activity leading to activation of PKA ( Dechant et al., 2010 ). Recently, valproate has been shown to decrease glycolytic flux resulting in both increased phosphorylation at T210, and decreased Pma1 activity ( Salsaa et al., 2021 ). Here we have shown that decreasing Pma1 activity is a requirement for Snf1 activation.…”

Section: Discussionmentioning

confidence: 99%

Regulation of yeast Snf1 (AMPK) by a polyhistidine containing pH sensing module

Simpson-Lavy

Kupiec

2022

iScience

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“…On the other hand, the ATPase activity of Pma1 is the major consumer of cellular ATP. There is plenty of evidence that a decrease in Pma1 activity either by means of pharmacological inhibition [66][67][68] or due to point mutations in the protein leading to partial defects in proton pumping [69] results in an increase in ATP levels. Such increase was also detected in parallel with Pma1 dephosphorylation in cells overexpressing Ppz1 [29], and this finding perfectly fits with the notion that Pma1 is inhibited when Ppz1 levels are high.…”

Section: The Alteration Of Monovalent Cation and Ph Homeostasis Contr...mentioning

confidence: 99%

When Phosphatases Go Mad: The Molecular Basis for Toxicity of Yeast Ppz1

Casamayor

Ariño

2022

IJMS

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The fact that overexpression of the yeast Ser/Thr protein phosphatase Ppz1 induces a dramatic halt in cell proliferation was known long ago, but only work in the last few years has provided insight into the molecular basis for this toxicity. Overexpression of Ppz1 causes abundant changes in gene expression and modifies the phosphorylation state of more than 150 proteins, including key signaling protein kinases such as Hog1 or Snf1. Diverse cellular processes are altered: halt in translation, failure to properly adapt to low glucose supply, acidification of the cytosol, or depletion of intracellular potassium content are a few examples. Therefore, the toxicity derived from an excess of Ppz1 appears to be multifactorial, the characteristic cell growth blockage thus arising from the combination of various altered processes. Notably, overexpression of the Ppz1 regulatory subunit Hal3 fully counteracts the toxic effects of the phosphatase, and this process involves intracellular relocation of the phosphatase to internal membranes.

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Valproate activates the Snf1 kinase in Saccharomyces cerevisiae by decreasing the cytosolic pH

Cited by 7 publications

References 84 publications

Phosphatidic acid inhibits inositol synthesis by inducing nuclear translocation of IP6K1 and repression of myo-inositol-3-P synthase

Phosphatidic acid inhibits inositol synthesis by inducing nuclear translocation of IP6K1 and repression of myo-inositol-3-P synthase

Regulation of yeast Snf1 (AMPK) by a polyhistidine containing pH sensing module

When Phosphatases Go Mad: The Molecular Basis for Toxicity of Yeast Ppz1

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