<i>Saccharomyces cerevisiae</i> TORC1 Controls Histone Acetylation by Signaling Through the Sit4/PP6 Phosphatase to Regulate Sirtuin Deacetylase Nuclear Accumulation

Workman, Jason J.; Chen, Hongfeng; Laribee, R. Nicholas

doi:10.1534/genetics.116.188458

Cited by 23 publications

(28 citation statements)

References 64 publications

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“…Then, we examined whether TORC1 signaling regulates PMA1 expression through Tap42‐regulated phosphatases. Mutants deleted for individual catalytic phosphatase subunits ( PP4/pph3∆ , PPG1/ppg1∆ , and PP6/sit4∆ ) of PP2A‐like protein phosphatases or the common regulatory subunit ( tpd3∆ ) of PP2A phosphatases (Hombauer et al, 2007; Workman, Chen, & Laribee, 2016) were generated and examined for the change in Pma1 protein level by rapamycin treatment. Rapamycin treatment reduced Pma1 protein level in the wild‐type and all phosphatase mutants, except for in the sit4∆ cells (Figure 5a), suggesting that the effect of TORC1 inhibition on PMA1 expression is achieved through Sit4.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

confidence: 99%

TORC1 signaling regulates cytoplasmic pH through Sir2 in yeast

et al. 2020

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“…Additionally, the network density between INO80 and both the Hst3 sirtuin histone deacetylase and SAGA histone acetyltransferase significantly increases in the presence of rapamycin (Figure 5C, bottom panel for Hst3 and data not shown, p = 0.00275, for SAGA). Both SAGA and Hst3 regulate the acetylation status of shared histone targets, the deacetylation of which is suppressed by TORC1 (Workman, Chen, & Laribee, 2016). Thus, the INO80 complex likely functions with different (de)acetylases depending on the metabolic environment.…”

Section: Resultsmentioning

confidence: 99%

“…To further investigate INO80’s maintenance of histone acetylation, we directly tested the effect of Ino80 loss on H3K18 acetylation (H3K18ac). We chose H3K18 because it is TORC1-responsive and deacetylated by Rpd3L and Hst3 (Workman et al, 2016). Additionally, H3K18ac and Arp5 have similar average distributions around +1 nucleosomes genome-wide (Figure 5 – figure supplement 1A ), thus are able to regulate the same genes.…”

Section: Resultsmentioning

confidence: 99%

The INO80 Chromatin Remodeler Sustains Metabolic Stability by Promoting TOR Signaling and Regulating Histone Acetylation

Beckwith

Schwartz

García-Nieto

et al. 2017

Preprint

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24Chromatin remodeling complexes are essential for gene expression programs that coordinate 25 cell function with metabolic status. However, how these remodelers are integrated in metabolic 26 stability pathways is not well known. Here, we report an expansive genetic screen with 27 chromatin remodelers and metabolic regulators in Saccharomyces cerevisiae. We found that, 28 unlike the SWR1 remodeler, the INO80 chromatin remodeling complex is composed of multiple 29 distinct functional subunit modules. We identified a strikingly divergent genetic signature for the 30 Ies6 subunit module that links the INO80 complex to metabolic homeostasis, including 31 mitochondrial maintenance. INO80 is also needed to communicate TORC1-mediated signaling 32 to chromatin and maintains histone acetylation at TORC1-responsive genes. Furthermore, 33 computational analysis reveals subunits of INO80 and mTORC1 have high co-occurrence of 34 alterations in human cancers. Collectively, these results demonstrate that the INO80 complex is35 a central component of metabolic homeostasis that influences histone acetylation and may 36 contribute to disease when disrupted. 37 38 101 homeostasis. These results place the INO80 complex as an important regulator of histone 102 modification that is downstream of TOR signaling. 103 104 105 RESULTS 106 107 An EMAP of chromatin and metabolic regulators 108Given the interplay between metabolism and epigenetics, we set out to comprehensively 109 identify shared pathways in which chromatin and metabolic regulators function in S. cerevisiae. 110To do this, we conducted an EMAP of unstressed and metabolically challenged cells grown on 111 rich media (untreated), rapamycin or ethanol, which generated approximately a quarter million 112 interactions (Figure 1A and Supplementary File 1). Rapamycin inhibits the TORC1 complex, a 113 master regulator of cellular growth (Loewith & Hall, 2011). Ethanol is a non-fermentable carbon 114 source that requires cells to utilize oxidative phosphorylation, whereas yeast preferentially 115 Beckwith et al. 6ferment glucose (Zaman, Lippman, Zhao, & Broach, 2008). We included a test library of 1536 116 alleles covering most major cellular processes, and significantly enriched for chromatin and 117 metabolic regulators (Ryan et al., 2012). We used 54 query strains that cover several chromatin 118 remodeling complexes, histone modifiers and metabolic signaling pathways (Figure 1B). 119 Our analyses also included deletions of all INO80's unique subunits and domain mutants 120 of INO80, ARP5 and IES6 (see Materials and Methods) because complete deletion resulted in 121 inconsistent colony growth in the EMAP process (data not shown), thus confounding our ability 122 to confidently determine genetic interactions. The resulting mutants disrupted the Arp8, Arp5 123 and Nhp10 structural modules of the INO80 complex (Figure 1 -figure supplement 1). 124Genetic interactions (S-scores) were calculated from the fitness of double mutants 125 ( Figure 1C, Figure 1 -figure supplement 2). Positiv...

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“…In fission yeast, SAGA control of cell proliferation and differentiation in response to starvation requires the differential TORC1/TORC2-dependent phosphorylation of the SAGA component Taf12 102 . TORC1 also regulates yeast histone acetylation by regulating the sirtuin deacetylases Hst3 and Hst4 103 and integrates signals through the INO80 chromatin remodeling complex 104 . Because of the breath of cellular functions affected by TORC1 and transcriptional regulators like SAGA, a comprehensive understanding on how these pathways converge to regulate homeostasis both in normal and disease states is crucial.…”

Section: Discussionmentioning

confidence: 99%

Sfp1 regulates the SAGA component Tra1 in response to proteotoxic stress inSaccharomyces cerevisiae

Jiang

Berg

Genereaux

et al. 2018

Preprint

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Proteotoxic stress triggers transcriptional responses that allow cells to compensate for the accumulation of toxic misfolded proteins. Chromatin remodeling regulates gene expression in response to the accumulation of misfolded polyQ proteins associated with Huntington’s disease (HD). Tra1 is an essential component of both the SAGA/SLIK and NuA4 transcription co-activator complexes and is linked to multiple cellular processes associated with misfolded protein stress, including the heat shock response. Cells with compromised Tra1 activity display phenotypes distinct from deletions encoding components of the SAGA and NuA4 complexes, indicating a potentially unique regulatory role of Tra1 in the cellular response to protein misfolding. Here, we employed a yeast model of HD to define how the expression of toxic polyQ expansion proteins affects Tra1 expression and function. Expression of expanded polyQ proteins, mimics deletion of SAGA/NuA4 components and results in growth defects under stress conditions. Moreover, deleting genes encoding SAGA and, to a lesser extent, NuA4 components exacerbates polyQ toxicity. Also, cells carrying a mutant Tra1 allele displayed increased sensitivity to polyQ toxicity. Interestingly, expression of polyQ proteins also upregulated the expression of TRA1 and other genes encoding SAGA components, revealing a feedback mechanism aimed at maintaining Tra1and SAGA functional integrity. Moreover, deleting the TORC1 (Target of Rapamycin) effector SFP1 specifically abolished upregulation of TRA1 upon expression of polyQ proteins. While Sfp1 is known to adjust ribosome biogenesis and cell size in response to stress, we identified a new role for Sfp1 in the control of Tra1, linking TORC1 and cell growth regulation to functions of the SAGA acetyltransferase complex during misfolded protein stress.

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Saccharomyces cerevisiae TORC1 Controls Histone Acetylation by Signaling Through the Sit4/PP6 Phosphatase to Regulate Sirtuin Deacetylase Nuclear Accumulation

Cited by 23 publications

References 64 publications

TORC1 signaling regulates cytoplasmic pH through Sir2 in yeast

TORC1 signaling regulates cytoplasmic pH through Sir2 in yeast

The INO80 Chromatin Remodeler Sustains Metabolic Stability by Promoting TOR Signaling and Regulating Histone Acetylation

Sfp1 regulates the SAGA component Tra1 in response to proteotoxic stress inSaccharomyces cerevisiae

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