Sfp1 links TORC1 and cell growth regulation to the yeast SAGA‐complex component Tra1 in response to polyQ proteotoxicity

Jiang, Yuwei; Berg, Matthew D.; Genereaux, Julie; Ahmed, Khadija; Duennwald, Martin L.; Brandl, Christopher J.; Lajoie, Patrick

doi:10.1111/tra.12637

“…We previously found that Tra1 regulates the expression of genes associated with several stress responses including cell wall stress and the response to misfolded proteins ( Berg et al 2018 ; Jiang et al 2019 ; Razzaq et al 2021 ). Based on findings that tra1 Q3 cells have a shorter lifespan, we next sought to determine how the loss of Tra1 function impacts the transcriptional landscape of the aging cell.…”

Section: Resultsmentioning

confidence: 99%

Tra1 controls the transcriptional landscape of the aging cell

Bari

¹

,

Berg

²

,

Genereaux

³

et al. 2022

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Gene expression undergoes considerable changes during the aging process. The mechanisms regulating the transcriptional response to cellular aging remain poorly understood. Here, we employ the budding yeast Saccharomyces cerevisiae to better understand how organisms adapt their transcriptome to promote longevity. Chronological lifespan (CLS) assays in yeast measure the survival of non-dividing cells at stationary phase over time, providing insights into the aging process of post-mitotic cells. Tra1 is an essential component of both the yeast SAGA/SLIK and NuA4 complexes, where it recruits these complexes to acetylate histones at targeted promoters. Importantly, Tra1 regulates the transcriptional response to multiple stresses. To evaluate the role of Tra1 in chronological aging, we took advantage of a previously characterized mutant allele that carries mutations in the TRA1 PI3K domain (tra1Q3). We found that loss of functions associated with tra1Q3 sensitized cells to growth media acidification and shortens lifespan. Transcriptional profiling reveals that genes differentially regulated by Tra1 during the aging process are enriched for components of the response to stress. Notably, expression of catalases (CTA1, CTT1) involved in hydrogen peroxide detoxification decreases in chronologically aged tra1Q3 cells. Consequently, they display increased sensitivity to oxidative stress. tra1Q3 cells are unable to grow on glycerol indicating a defect in mitochondria function. Aged tra1Q3 cells also display reduced expression of peroxisomal genes, exhibit decreased numbers of peroxisomes and cannot grow on media containing oleate. Thus, Tra1 emerges as an important regulator of longevity in yeast via multiple mechanisms.

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“…We previously found that Tra1 regulates the expression of genes associated with several stress responses including cell wall stress and the response to misfolded proteins (Berg et al . 2018; Jiang et al . 2019; Razzaq et al .…”

Section: Resultsmentioning

confidence: 99%

Tra1 controls the transcriptional landscape of the aging cell

Bari

¹

,

Berg

²

,

Genereaux

³

et al. 2022

Preprint

Self Cite

0

View full text Add to dashboard Cite

Gene expression undergoes considerable changes during the aging process. The mechanisms regulating the transcriptional response to cellular aging remain poorly understood. Here, we employ the budding yeast Saccharomyces cerevisiae to better understand how organisms adapt their transcriptome to promote longevity. Chronological lifespan (CLS) assays in yeast measure the survival of non-dividing cells at stationary phase over time, providing insights into the aging process of post-mitotic cells. Tra1 is an essential component of both the yeast SAGA/SLIK and NuA4 complexes, where it recruits these complexes to acetylate histones at targeted promoters. Importantly, Tra1 regulates the transcriptional response to multiple stresses. To evaluate the role of Tra1 in chronological aging, we took advantage of a previously characterized mutant allele that carries mutations in the TRA1 PI3K domain (tra1Q3). We found that loss of functions associated with tra1Q3 sensitized cells to growth media acidification and shortens lifespan. Transcriptional profiling reveals that genes differentially regulated by Tra1 during the aging process are enriched for components of the response to stress. Notably, expression of catalases (CTA1, CTT1) involved in hydrogen peroxide detoxification decreases in chronologically aged tra1Q3 cells. Consequently, they display increased sensitivity to oxidative stress. tra1Q3 cells are unable to grow on glycerol indicating a defect in mitochondria function. Aged tra1Q3 cells also display reduced expression of peroxisomal genes, exhibit decreased numbers of peroxisomes and cannot grow on media containing oleate. Thus, Tra1 emerges as an important regulator of longevity in yeast via multiple mechanisms.

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“…Interestingly, our analysis also shows significant enrichment in Sfp1 target genes and RLM1 targets ( FIGURE 1e ). Sfp1 interacts with Tra1 (68) and we recently demonstrated that Sfp1 regulates Tra1/SAGA-driven gene expression in response to protein misfolding (69). RLM1 controls gene expression of factors involved in the cell wall integrity pathway (CWI) (64), consistent with the tra1 Q3 causing increased sensitivity to cell wall perturbation (47).…”

Section: Resultsmentioning

confidence: 99%

The SAGA and NuA4 component Tra1 regulatesCandida albicansdrug resistance and pathogenesis

Razzaq

¹

,

Berg

²

,

Jiang

³

et al. 2021

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Candida albicans is the most common cause of death from fungal infections. Emergence of resistant strains reducing the efficacy of first line therapy with echinocandins such as caspofungin calls for the identification of alternative therapeutic strategies. Tra1 is an essential component of the SAGA and NuA4 transcriptional co-activator complexes. As a PIKK family member, Tra1 is characterized by a C-terminal phosphoinositide 3-kinase domain. In Saccharomyces cerevisiae, the assembly and function of SAGA and NuA4 is compromised by a version of Tra1 (Tra1Q3) with three arginine residues in the putative ATP-binding cleft changed to glutamine, Whole transcriptome analysis of the S. cerevisiae tra1Q3 strain highlights Tra1’s role in global transcription, stress response and cell wall integrity. As a result, tra1Q3 increases susceptibility to multiple stressors, including caspofungin. Moreover, the same tra1Q3 allele in the pathogenic yeast Candida albicans causes similar phenotypes, suggesting that Tra1 broadly mediates the antifungal response across yeast species. Transcriptional profiling in C. albicans identified 68 genes that were differentially expressed when the tra1Q3 strain was treated with caspofungin, as compared to gene expression changes induced by either tra1Q3 or caspofungin alone. Included in this set were genes involved in cell wall maintenance, adhesion and filamentous growth. Indeed, the tra1Q3 allele reduces filamentation and other pathogenesis traits in C. albicans. We identified EVP1, which encodes a putative plasma membrane protein, amongst the Tra1-regulated genes, Disrupting EVP1 results in reduced filamentation and infection capacity in C. albicans. Thus,Tra1 emerges as a promising therapeutic target for fungal infections.ImportanceFungal pathogens such as Candida albicans are important agents of infectious disease, with increasing rates of drug resistance, and limited available antifungal therapeutics. In this study, we characterize the role of C. albicans Tra1, a critical component of acetyltransferase complexes, involved in transcriptional regulation and responses to environmental stress. We find C. albicans genetic mutants with impaired Tra1 function have reduced tolerance to cell-wall targeting stressors, including the clinically-important antifungal caspofungin. We further use RNA-sequencing to profile the global fungal response to the tra1 mutation, and identify a previously uncharacterized C. albicans gene, EVP1. We find that both TRA1 and EVP1 play an important role in phenotypes associated with fungal pathogenesis, including cellular morphogenesis, biofilm formation, and toxicity towards host immune cells. Together, this work describes the key role for Tra1 in regulating fungal drug tolerance and pathogenesis, and positions this protein as a promising therapeutic target for fungal infections.

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Sfp1 links TORC1 and cell growth regulation to the yeast SAGA‐complex component Tra1 in response to polyQ proteotoxicity

Cited by 9 publications

References 135 publications

Tra1 controls the transcriptional landscape of the aging cell

Tra1 controls the transcriptional landscape of the aging cell

Tra1 controls the transcriptional landscape of the aging cell

The SAGA and NuA4 component Tra1 regulatesCandida albicansdrug resistance and pathogenesis

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