Title: Characterization of multidrug resistance transporters in the model organisms Saccharomyces cerevisiae and Arabidopsis thaliana: establishing a link between physiological role and action in chemical stress tolerance.
Abstract: The emergence of multidrug resistance (MDR) is frequently due to the action of MDR transporters that presumably catalyze the extrusion of several unrelated chemicals. However, their action has been proposed to, at least partially, rely on the transport of physiological substrate(s), indirectly affecting drug partition or transport across cell membranes (Sá-Correia et al., 2009).
In this thesis, a physiological role was attributed to two Saccharomyces cerevisiae MDR transporters: the drug:H+ antiporter Qdr3 and the ATP Binding-Cassette transporter Pdr18. Qdr3 was shown to play a role in polyamine homeostasis, its expression decreasing the intracellular accumulation of 3H-spermidine and controlling plasma membrane potential in spermidine stressed cells (Cabrito et al., 2011a). Pdr18 was found to mediate plasma membrane ergosterol incorporation, affecting plasma membrane potential. The action of Pdr18p in yeast tolerance to the herbicide 2,4-Dichlorophenoxyacetic acid is proposed to be indirect, given that under 2,4-D stress the ergosterol plasma membrane content is reduced, especially in pdr18 background (Cabrito et al., 2011b).
Results obtained in yeast guided the functional analysis of Arabidopsis thalianauncharacterized putative MFS transporters At5g13750 (Zifl1) (Cabrito et al., 2009; Remyet al., 2013) and At3g43790 (Zifl2). These transporters were shown to affect K+ and auxin homeostasis, contributing to hypocotyl and root elongation, to gravitropism and water loss control and to confer resistance multiple xenobiotic compounds (Remy et al., 2013).
Acknowledgments: This study was financially supported by “Fundação para a Ciência e a Tecnologia” (contracts PTDC/AGR-AAM/67858/2006, PTDC/BIA-MIC/72577/2006, PTDC/AGR-AAM/102967/2008 and PhD grant SFRH/BD/40885/2007).
Sá-Correia I, Santos SR, Teixeira MC, Cabrito TR, Mira NP. 2009 Drug:H+antiporters in chemical stress response in yeast. Trends Microbiol. 17: 22-31.
Cabrito TR, Teixeira MC, Hanif ZM, Vargas RC, Tenreiro S, Sá-Correia I. (2011a), Yeast response and tolerance to polyamine toxicity involving the drug:H+antiporter Qdr3 and the transcription factors Yap1 and Gcn4. Microbiology. 157: 945-956.
Cabrito TR, Teixeira MC, Singh A, Prasad P, Sá-Correia I. (2011b), The yeast ABC transporter Pdr18 (ORF YNR070w) controls plasma membrane sterol composition, playing a role in multidrug resistance. Biochem. J. 440: 195-202.
Cabrito TR, Teixeira MC, Duarte AA, Duque P, Sá-Correia I. (2009), Heterologous expression of a Tpo1 homolog from Arabidopsis thaliana confers resistance to the herbicide 2,4-D and other chemical stresses in yeast. Appl.Microbiol. Biotechnol. 84: 927-936.
Remy E, Cabrito TR, Batista R, Teixeira MC, Sá-Correia I, Duque P. (2013), A Major Facilitator Superfamily Transporter Plays a Dual Role in Auxin Transport and Drought Tolerance in Arabidopsis. The Plant Cell (accepted for publication).
PhD Degree: Biotechnology; Year of conlusion: 2011
Institution: Instituto Superior Técnico, Universidade Técnica de Lisboa
Supervision: Isabel Sá-Correia and Miguel Cacho Teixeira