Abstract
Saccharomyces cerevisiae has the ability to become less sensitive to a broad range of chemically and functionally unrelated cytotoxic compounds. Among multistress resistance mechanisms is the one mediated by plasma membrane efflux pump proteins belonging to the ABC superfamily, questionably proposed to enhance the kinetics of extrusion of all these compounds. This study provides new insights into the biological role and impact in yeast response to acetic acid stress of the multistress resistance determinant Pdr18 proposed to mediate ergosterol incorporation in plasma membrane. The described coordinated activation of the transcription of PDR18 and of several ergosterol biosynthetic genes (ERG2-4, ERG6, ERG24) during the period of adaptation to acetic acid inhibited growth provides further support to the involvement of Pdr18 in yeast response to maintain plasma membrane ergosterol content in stressed cells. Pdr18 role in ergosterol homeostasis helps the cell to counteract acetic acid-induced decrease of plasma membrane lipid order, increase of the non-specific membrane permeability and decrease of transmembrane electrochemical potential. Collectively, our results support the notion that Pdr18-mediated multistress resistance is closely linked to the status of plasma membrane lipid environment related with ergosterol content and the associated plasma membrane properties.
Highlights
The acquisition of multidrug/multixenobiotic resistance (MDR/MXR) is widespread in nature and has clinical, agricultural and biotechnological implications
The expression of the ATP-binding cassette plasma membrane transporter encoding gene PDR18 was found to be required to partially overcome the effects of acetic acid induced stress in yeast growth (Figs 2 and 3). Susceptibility towards this weak acid was assessed based on yeast growth in liquid medium by comparing the growth of a parental strain Saccharomyces cerevisiae BY4741 and the derived deletion mutant pdr18Δ exposed to a wide range of acetic acid concentrations and determining the minimum inhibitory concentration (MIC) (Fig. 2)
The final biomass attained after yeast cultivation under acetic acid stress showed a dose-dependent decrease and was more evident for the pdr18Δ mutant (Fig. 2)
Summary
The acquisition of multidrug/multixenobiotic resistance (MDR/MXR) is widespread in nature and has clinical, agricultural and biotechnological implications. Two of the described MDR/MXR transporter families occur in all classes of organisms and belong to the ATP binding cassette (ABC) superfamily, which uses the hydrolysis of ATP to translocate a variety of solutes across biological membranes[2,3], or to the Major Facilitator Superfamily (MFS) which energetically drive their transport utilizing the transmembrane electrochemical gradient[1,4] Those proteins have been traditionally considered drug exporters, their physiological function and the exact mechanism of their involvement in resistance to cytotoxic compounds are still unclear and it is puzzling that a wide range of structurally and functionally unrelated substrates may be exported by a specific transporter. The content of ergosterol is crucial for plasma membrane stability and adequate selective permeability barrier to avoid the passive diffusion of toxic compounds into the cell[48,49], but is related with the formation of lipid-raft domains that may modulate the activity of membrane-embedded pumps[50,51]
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