The yeast ABC transporter Pdr18 (ORF YNR070w) controls plasma membrane sterol composition, playing a role in multidrug resistance
Résumé
The action of multidrug efflux pumps in multidrug resistance (MDR) acquisition has been proposed to partially depend on the transport of physiological substrates which may indirectly affect drug partition and transport across cell membranes. In this work, PDR18 gene (ORF YNR070w), encoding a putative pleiotropic drug resistance (PDR) transporter of the ATP-binding cassette superfamily, was found to mediate plasma membrane sterol incorporation in yeast. Pdr18 physiological role is demonstrated to affect plasma membrane potential and is proposed to underlie its action as a MDR determinant, conferring resistance to the herbicide 2,4-D. The action of Pdr18 in yeast tolerance to 2,4-D, which was found to contribute to reduce [14C]-2,4-D intracellular accumulation, may be indirect, given the observation that 2,4-D exposure deeply affects the sterol plasma membrane composition, this effect being much stronger in Dpdr18 background. PDR18 activation under 2,4-D stress is regulated by the transcription factors Nrg1, controlling carbon source availability and stress response, and, less significantly, Yap1, involved in oxidative stress and MDR, and Pdr3, a key regulator of the yeast PDR network, consistent with a broad role in stress defence. Altogether, our results suggest that Pdr18 plays a role in plasma membrane sterol incorporation, this physiological trait contributing to a MDR phenotype.
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