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Deteriorated stress response in stationary-phase yeast: Sir2 and Yap1 are essential for Hsf1 activation by heat shock and oxidative stress, respectively.

Nussbaum I, Weindling E, Jubran R, Cohen A, Bar-Nun S - PLoS ONE (2014)

Bottom Line: However, the molecular processes underlying stress response of non-dividing cells are poorly understood, although deteriorated stress response is one of the hallmarks of aging.This response is orchestrated largely by the conserved transcription factor Hsf1, which in S. cerevisiae regulates expression of multiple genes in response to diverse stresses.Rather, factors that participate in Hsf1 activation appear to be compromised.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
Stationary-phase cultures have been used as an important model of aging, a complex process involving multiple pathways and signaling networks. However, the molecular processes underlying stress response of non-dividing cells are poorly understood, although deteriorated stress response is one of the hallmarks of aging. The budding yeast Saccharomyces cerevisiae is a valuable model organism to study the genetics of aging, because yeast ages within days and are amenable to genetic manipulations. As a unicellular organism, yeast has evolved robust systems to respond to environmental challenges. This response is orchestrated largely by the conserved transcription factor Hsf1, which in S. cerevisiae regulates expression of multiple genes in response to diverse stresses. Here we demonstrate that Hsf1 response to heat shock and oxidative stress deteriorates during yeast transition from exponential growth to stationary-phase, whereas Hsf1 activation by glucose starvation is maintained. Overexpressing Hsf1 does not significantly improve heat shock response, indicating that Hsf1 dwindling is not the major cause for Hsf1 attenuated response in stationary-phase yeast. Rather, factors that participate in Hsf1 activation appear to be compromised. We uncover two factors, Yap1 and Sir2, which discretely function in Hsf1 activation by oxidative stress and heat shock. In Δyap1 mutant, Hsf1 does not respond to oxidative stress, while in Δsir2 mutant, Hsf1 does not respond to heat shock. Moreover, excess Sir2 mimics the heat shock response. This role of the NAD+-dependent Sir2 is supported by our finding that supplementing NAD+ precursors improves Hsf1 heat shock response in stationary-phase yeast, especially when combined with expression of excess Sir2. Finally, the combination of excess Hsf1, excess Sir2 and NAD+ precursors rejuvenates the heat shock response.

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Related in: MedlinePlus

A schematic presentations of the various Hsf1 activation pathways.The three stresses, heat shock, oxidative stress and sugar starvation, activate the inactive Hsf1 through different mediators, Sir2, Yap1 and Snf1, respectively. Consequently, three distinct types of active Hsf1 are generated, HSF1HS, Hsf1OS and Hsf1SS, respectively. These, in turn, transactivate the transcription of the indicated subsets of target genes.
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pone-0111505-g009: A schematic presentations of the various Hsf1 activation pathways.The three stresses, heat shock, oxidative stress and sugar starvation, activate the inactive Hsf1 through different mediators, Sir2, Yap1 and Snf1, respectively. Consequently, three distinct types of active Hsf1 are generated, HSF1HS, Hsf1OS and Hsf1SS, respectively. These, in turn, transactivate the transcription of the indicated subsets of target genes.

Mentions: The current studies establish Hsf1 as a longevity-related gene also in yeast, as its activation by heat shock or oxidative stress deteriorates in stationary-phase cells. We also provide evidence for two mediators of Hsf1 activation, Sir2 and Yap1, which operate in two discrete activation pathways: Sir2 in the heat shock response and Yap1 in the oxidative stress response (Figure 9). Our direct measurements of Hsf1 activity are based on three reporters with distinct HSEs, which respond differently to the three stressors tested. All three reporters respond to heat shock by increasing the levels of the proteins encoded by them. However, only HSE2-lacZ, driven by the synthetic HSE, is activated by oxidative stress yet it is indifferent to glucose starvation. Conversely, the genes driven by the perfect type endogenous HSEs, HSP26 and BTN2, are activated by glucose starvation, but are indifferent to oxidative stress. This differential reaction to stress challenges emphasizes the specificity and modularity of the Hsf1 response, which is reflected by distinct subsets of responsive genes but more importantly, by unique modes of Hsf1 activation (Figure 9).


Deteriorated stress response in stationary-phase yeast: Sir2 and Yap1 are essential for Hsf1 activation by heat shock and oxidative stress, respectively.

Nussbaum I, Weindling E, Jubran R, Cohen A, Bar-Nun S - PLoS ONE (2014)

A schematic presentations of the various Hsf1 activation pathways.The three stresses, heat shock, oxidative stress and sugar starvation, activate the inactive Hsf1 through different mediators, Sir2, Yap1 and Snf1, respectively. Consequently, three distinct types of active Hsf1 are generated, HSF1HS, Hsf1OS and Hsf1SS, respectively. These, in turn, transactivate the transcription of the indicated subsets of target genes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214751&req=5

pone-0111505-g009: A schematic presentations of the various Hsf1 activation pathways.The three stresses, heat shock, oxidative stress and sugar starvation, activate the inactive Hsf1 through different mediators, Sir2, Yap1 and Snf1, respectively. Consequently, three distinct types of active Hsf1 are generated, HSF1HS, Hsf1OS and Hsf1SS, respectively. These, in turn, transactivate the transcription of the indicated subsets of target genes.
Mentions: The current studies establish Hsf1 as a longevity-related gene also in yeast, as its activation by heat shock or oxidative stress deteriorates in stationary-phase cells. We also provide evidence for two mediators of Hsf1 activation, Sir2 and Yap1, which operate in two discrete activation pathways: Sir2 in the heat shock response and Yap1 in the oxidative stress response (Figure 9). Our direct measurements of Hsf1 activity are based on three reporters with distinct HSEs, which respond differently to the three stressors tested. All three reporters respond to heat shock by increasing the levels of the proteins encoded by them. However, only HSE2-lacZ, driven by the synthetic HSE, is activated by oxidative stress yet it is indifferent to glucose starvation. Conversely, the genes driven by the perfect type endogenous HSEs, HSP26 and BTN2, are activated by glucose starvation, but are indifferent to oxidative stress. This differential reaction to stress challenges emphasizes the specificity and modularity of the Hsf1 response, which is reflected by distinct subsets of responsive genes but more importantly, by unique modes of Hsf1 activation (Figure 9).

Bottom Line: However, the molecular processes underlying stress response of non-dividing cells are poorly understood, although deteriorated stress response is one of the hallmarks of aging.This response is orchestrated largely by the conserved transcription factor Hsf1, which in S. cerevisiae regulates expression of multiple genes in response to diverse stresses.Rather, factors that participate in Hsf1 activation appear to be compromised.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
Stationary-phase cultures have been used as an important model of aging, a complex process involving multiple pathways and signaling networks. However, the molecular processes underlying stress response of non-dividing cells are poorly understood, although deteriorated stress response is one of the hallmarks of aging. The budding yeast Saccharomyces cerevisiae is a valuable model organism to study the genetics of aging, because yeast ages within days and are amenable to genetic manipulations. As a unicellular organism, yeast has evolved robust systems to respond to environmental challenges. This response is orchestrated largely by the conserved transcription factor Hsf1, which in S. cerevisiae regulates expression of multiple genes in response to diverse stresses. Here we demonstrate that Hsf1 response to heat shock and oxidative stress deteriorates during yeast transition from exponential growth to stationary-phase, whereas Hsf1 activation by glucose starvation is maintained. Overexpressing Hsf1 does not significantly improve heat shock response, indicating that Hsf1 dwindling is not the major cause for Hsf1 attenuated response in stationary-phase yeast. Rather, factors that participate in Hsf1 activation appear to be compromised. We uncover two factors, Yap1 and Sir2, which discretely function in Hsf1 activation by oxidative stress and heat shock. In Δyap1 mutant, Hsf1 does not respond to oxidative stress, while in Δsir2 mutant, Hsf1 does not respond to heat shock. Moreover, excess Sir2 mimics the heat shock response. This role of the NAD+-dependent Sir2 is supported by our finding that supplementing NAD+ precursors improves Hsf1 heat shock response in stationary-phase yeast, especially when combined with expression of excess Sir2. Finally, the combination of excess Hsf1, excess Sir2 and NAD+ precursors rejuvenates the heat shock response.

Show MeSH
Related in: MedlinePlus