Control of Plasma Membrane Permeability by ABC Transporters

Svetlana Khakhina; Soraya S Johnson; Raman Manoharlal; Sarah B Russo; Corinne Blugeon; Sophie Lemoine; Anna B Sunshine; Maitreya J Dunham; L Ashley Cowart; Frédéric Devaux; W Scott Moye-Rowley

doi:10.1128/EC.00021-15

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Control of Plasma Membrane Permeability by ABC Transporters

Journal article

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Peer reviewed

Control of Plasma Membrane Permeability by ABC Transporters

Svetlana Khakhina, Soraya S Johnson, Raman Manoharlal, Sarah B Russo, Corinne Blugeon, Sophie Lemoine, Anna B Sunshine, Maitreya J Dunham, L Ashley Cowart, Frédéric Devaux, …

Eukaryotic cell, Vol.14(5), pp.442-453

05/2015

DOI: 10.1128/EC.00021-15

PMCID: PMC4421010

PMID: 25724885

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Abstract

ATP-binding cassette transporters Pdr5 and Yor1 from Saccharomyces cerevisiae control the asymmetric distribution of phospholipids across the plasma membrane as well as serving as ATP-dependent drug efflux pumps. Mutant strains lacking these transporter proteins were found to exhibit very different resistance phenotypes to two inhibitors of sphingolipid biosynthesis that act either late (aureobasidin A [AbA]) or early (myriocin [Myr]) in the pathway leading to production of these important plasma membrane lipids. These pdr5Δ yor1 strains were highly AbA resistant but extremely sensitive to Myr. We provide evidence that these phenotypic changes are likely due to modulation of the plasma membrane flippase complexes, Dnf1/Lem3 and Dnf2/Lem3. Flippases act to move phospholipids from the outer to the inner leaflet of the plasma membrane. Genetic analyses indicate that lem3Δ mutant strains are highly AbA sensitive and Myr resistant. These phenotypes are fully epistatic to those seen in pdr5Δ yor1 strains. Direct analysis of AbA-induced signaling demonstrated that loss of Pdr5 and Yor1 inhibited the AbA-triggered phosphorylation of the AGC kinase Ypk1 and its substrate Orm1. Microarray experiments found that a pdr5Δ yor1 strain induced a Pdr1-dependent induction of the entire Pdr regulon. Our data support the view that Pdr5/Yor1 negatively regulate flippase function and activity of the nuclear Pdr1 transcription factor. Together, these data argue that the interaction of the ABC transporters Pdr5 and Yor1 with the Lem3-dependent flippases regulates permeability of AbA via control of plasma membrane protein function as seen for the high-affinity tryptophan permease Tat2.

Gene Expression Regulation, Fungal

Saccharomyces cerevisiae - metabolism

Transcription Factors - metabolism

Cell Membrane Permeability - physiology

Saccharomyces cerevisiae Proteins - metabolism

ATP-Binding Cassette Transporters - metabolism

Trans-Activators - metabolism

Details

Title: Subtitle: Control of Plasma Membrane Permeability by ABC Transporters
Creators: Svetlana Khakhina - Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Soraya S Johnson - Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Raman Manoharlal - Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Sarah B Russo - Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
Corinne Blugeon - École Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Paris, France INSERM, U1024, Paris, France CNRS, UMR 8197, Paris, France
Sophie Lemoine - École Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Paris, France INSERM, U1024, Paris, France CNRS, UMR 8197, Paris, France
Anna B Sunshine - Department of Genome Sciences, University of Washington, Seattle, Washington, USA
Maitreya J Dunham - Department of Genome Sciences, University of Washington, Seattle, Washington, USA
L Ashley Cowart - Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
Frédéric Devaux - Sorbonne Universités, UPMC Universite Paris 06, UMR 7238, Laboratoire de Biologie Computationnelle et Quantitative, Paris, France CNRS, UMR 7238, Laboratoire de Biologie Computationnelle et Quantitative, Paris, France
W Scott Moye-Rowley - Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA scott-moye-rowley@uiowa.edu
Resource Type: Journal article
Publication Details: Eukaryotic cell, Vol.14(5), pp.442-453
DOI: 10.1128/EC.00021-15
PMID: 25724885
PMCID: PMC4421010
NLM abbreviation: Eukaryot Cell
ISSN: 1535-9778
eISSN: 1535-9786
Publisher: American Society for Microbiology; United States
Grant note: P41 GM103533 / NIGMS NIH HHS GM49825 / NIGMS NIH HHS T32 GM007266 / NIGMS NIH HHS R01 GM049825 / NIGMS NIH HHS F30 CA165440 / NCI NIH HHS R01 HL117233 / NHLBI NIH HHS T32 AG000057 / NIA NIH HHS
Language: English
Date published: 05/2015
Academic Unit: Molecular Physiology and Biophysics; Internal Medicine
Record Identifier: 9984025475102771

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