Adaptive Response and Tolerance to Weak Acids inSaccharomyces cerevisiae: A Genome-Wide View

Abstract

Weak acids are widely used as food preservatives (e.g., acetic, propionic, benzoic, and sorbic acids), herbicides (e.g., 2,4-dichlorophenoxyacetic acid), and as antimalarial (e.g., artesunic and artemisinic acids), anticancer (e.g., artesunic acid), and immunosuppressive (e.g., mycophenolic acid) drugs, among other possible applications. The understanding of the mechanisms underlying the adaptive response and resistance to these weak acids is a prerequisite to develop more effective strategies to control spoilage yeasts, and the emergence of resistant weeds, drug resistant parasites or cancer cells. Furthermore, the identification of toxicity mechanisms and resistance determinants to weak acid-based pharmaceuticals increases current knowledge on their cytotoxic effects and may lead to the identification of new drug targets. This review integrates current knowledge on the mechanisms of toxicity and tolerance to weak acid stress obtained in the model eukaryote Saccharomyces cerevisiae using genome-wide approaches and more detailed gene-by-gene analysis. The major features of the yeast response to weak acids in general, and the more specific responses and resistance mechanisms towards a specific weak acid or a group of weak acids, depending on the chemical nature of the side chain R group (R-COOH), are highlighted. The involvement of several transcriptional regulatory networks in the genomic response to different weak acids is discussed, focusing on the regulatory pathways controlled by the transcription factors Msn2p/Msn4p, War1p, Haa1p, Rim101p, and Pdr1p/Pdr3p, which are known to orchestrate weak acid stress response in yeast. The extrapolation of the knowledge gathered in yeast to other eukaryotes is also attempted.

Acetate but not propionate induces oxidative stress in bakers’ yeastSaccharomyces cerevisiae

“…14 Recent works reported that both Pdr12p and Yap1p are members of the Haa1p-regulon responsive to AA. 5,40 Results presented in Fig. 5 indicate that Yap1p is at least partially responsible for yeast survival under stress induced by AA.…”

“…It is well known that WOA toxicity is essentially determined by their hydrophobicity and pK a . 5 Although both AA and PA are hydrophilic and have quite close pK a , PA was more toxic to yeast at low concentrations and less toxic at high concentrations relative to AA. Earlier it was also found that S. cerevisiae demonstrated higher sensitivity to low doses of PA comparing with AA.…”

“…17,39 It was believed that expression of Pdr12p is controlled by the sole War1p transcriptional factor. 17 To date, it is well documented that weak acid stress-induced response depends on the following transcription factors: War1p, Msn2/Msn4p, Rim101p, and Haa1p, 5,38 and the sole War1p-target gene, PDR12, was identified among the genes activated by Haa1p in response to AA. 40 Analysis of these controversial data demonstrates that possible role of the Pdr12p involvement in acetate efflux is still an open problem.…”

“…The yeast Saccharomyces cerevisiae is a good model system to investigate acid stress and defense against it in eukaryotes, since its protective mechanisms are generally similar to those of higher organisms. [1][2][3][4][5][6] It was found that WOAs were mutagenic towards the mitochondrial genome in aerobically grown baker's yeast. 2 Accumulation of acid anions in the yeast cells also resulted in energetic stress, 7 programmed cell death, [8][9][10][11][12] and inhibition of essential metabolic pathways.…”

“…For example, yeast exposed to a mild dose of oxidative stress could subsequently survive an otherwise lethal dose of the same or another stress. 5,6,[23][24][25] The latter is known as 'cross-adaptation' or 'cross-protection'. In the present work, we examined the influence of cell pre-adaptation by sublethal concentrations of hydrogen peroxide on yeast survival under acid stress.…”