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

PLoS One. 2014 Oct 30;9(10):e111505. doi: 10.1371/journal.pone.0111505. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Binding Proteins / metabolism
  • Glucose / pharmacology
  • Heat-Shock Proteins / metabolism
  • Heat-Shock Response* / drug effects
  • Models, Biological
  • NAD / metabolism
  • Oxidative Stress* / drug effects
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / growth & development*
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae / metabolism
  • Sirtuin 2 / metabolism
  • Transcription Factors / metabolism

Substances

  • DNA-Binding Proteins
  • HSF1 protein, S cerevisiae
  • Heat-Shock Proteins
  • Saccharomyces cerevisiae Proteins
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae
  • Transcription Factors
  • YAP1 protein, S cerevisiae
  • NAD
  • SIR2 protein, S cerevisiae
  • Sirtuin 2
  • Glucose

Grants and funding

Israel Science Foundation (www.isf.org.il) grant no. 384/11. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.