TORC1 and TORC2 converge to regulate the SAGA co‐activator in response to nutrient availability

Laboucarié, Thomas; Detilleux, Dylane; Rodriguez‐Mias, Ricard A.; Faux, Céline; Roméo, Yves; Franz‐Wachtel, Mirita; Krug, Karsten; Maček, Boris; Villén, Judit; Petersen, Janni; Helmlinger, Dominique

doi:10.15252/embr.201744942

Cited by 47 publications

(68 citation statements)

References 103 publications

(153 reference statements)

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“…As a whole, we propose that hyperactivation of TORC1 signaling alters cell wall composition, sensitizing cells to ER stress‐causing agents such as antifungal drugs and changes in lipid homeostasis. Interestingly, previous studies have proposed a link between the functions of TORC1 signaling and the SAGA transcription co‐activator complex . SAGA‐dependent transcription is required for both proper expression of INO1 and activation of the CWI pathway transcriptional program .…”

Section: Resultsmentioning

confidence: 99%

Hyperactive TORC1 sensitizes yeast cells to endoplasmic reticulum stress by compromising cell wall integrity

2019

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Edited by Michael IbbaAccumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR). Here, we investigated how the target of rapamycin complex 1 (TORC1) signaling cascade acts in parallel with the UPR to regulate ER stress sensitivity. Using Saccharomyces cerevisiae, we found that TORC1 signaling is attenuated during ER stress and constitutive activation of TORC1 increases sensitivity to ER stressors independently of the UPR. Transcriptome analysis revealed that TORC1 hyperactivation results in cell wall remodelling. Conversely, hyperactive TORC1 sensitizes cells to cell wall stressors, including the antifungal caspofungin. Elucidating the crosstalk between the UPR, cell wall integrity, and TORC1 signaling may uncover new paradigms through which the response to protein misfolding is regulated.

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Section: Resultsmentioning

confidence: 99%

Hyperactive TORC1 sensitizes yeast cells to endoplasmic reticulum stress by compromising cell wall integrity

2019

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“…A TRA1 mutant allele is hypersensitive to rapamycin and results in a synthetic slow growth phenotype with tor1 deletion 47 . 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 .…”

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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“…Reverse transcription and quantitative PCR analyses of cDNA were performed using RNA extracted from 50 mL of exponentially growing cells, as described in (Laboucarié et al, 2017), and according to the MIQE guidelines (Bustin et al, 2009). Briefly, total RNA was purified using hot, acidic phenol and contaminating DNA was removed by DNase I digestion, using the TURBO DNA-free™ kit (AM1907, Ambion).…”

Section: Rt-qpcr Analysismentioning

confidence: 99%

“…Protein extracts were prepared as described in (Laboucarié et al, 2017). Briefly, 10 to 25 mL cultures of exponentially growing cells were homogenized by glass bead-beating in a FastPrep (MP Biomedicals).…”

Section: Protein Extractionmentioning

confidence: 99%

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Chaperone-mediated ordered assembly of the SAGA and NuA4 transcription co-activator complexes

Elías-Villalobos

Toullec

Faux

et al. 2019

Preprint

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Transcription initiation involves the coordinated activities of large multimeric complexes.Little is known about the mechanisms and pathways that drive their assembly from individual components. We report here several principles underlying the assembly of the highly conserved SAGA co-activator complex, which is composed of 19 subunits organized into functional modules. First, we demonstrate that SAGA assembles through an ordered pathway, in which the core subunit Spt20 recruits Tra1, which then promotes the incorporation of the de-ubiquitination module (DUB). Second, affinity purifications and phenotypic analyses identified a small region of Spt20 that is both necessary and sufficient to anchor Tra1 to SAGA. Third, Tra1 is shared with the NuA4 co-activator complex and is the only pseudokinase of the PIKK family. We accumulated functional and biochemical evidence that Tra1 shares a specific Hsp90 cochaperone with PIKKs, the Triple-T complex, for its cotranslational folding and de novo incorporation into both SAGA and NuA4. Finally, in contrast to its specific role in SAGA assembly, Tra1 contributes to scaffold the entire NuA4 complex. Overall, our study brings mechanistic insights into the de novo assembly of transcriptional complexes via ordered pathways and reveals the contribution of dedicated chaperones to this process.

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TORC1 and TORC2 converge to regulate the SAGA co‐activator in response to nutrient availability

Cited by 47 publications

References 103 publications

Hyperactive TORC1 sensitizes yeast cells to endoplasmic reticulum stress by compromising cell wall integrity

Hyperactive TORC1 sensitizes yeast cells to endoplasmic reticulum stress by compromising cell wall integrity

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

Chaperone-mediated ordered assembly of the SAGA and NuA4 transcription co-activator complexes

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