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Pdr5-mediated multidrug resistance requires the CPY-vacuolar sorting protein Vps3: are xenobiotic compounds routed from the vacuole to plasma membrane transporters for efflux?

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Pdr5-mediated multidrug resistance requires the CPY-vacuolar sorting protein Vps3: are xenobiotic compounds routed from the vacuole to plasma membrane transporters for efflux?

Content Provider	Springer Nature Link
Author	Rutledge, Robert M. Ghislain, Michel Mullins, J. Michael Thozée, Cedric Pety Golin, John
Copyright Year	2008
Abstract	In Saccharomyces cerevisiae several members of the ATP-binding cassette transporter superfamily efflux a broad range of xenobiotic substrates from cells. The vacuole also plays a critical role in multidrug resistance. Mutations in genes such as VPS3 that are essential for vacuolar acidification and carboxypeptidase Y vacuolar protein-sorting are multidrug sensitive. A similar phenotype is also observed with deletions of VPS15, VPS34, and VPS38, which encode essential members of the carboxypeptidase Y vacuolar protein–sorting pathway. Prior to the work described herein, detoxification by transporters and the vacuole were presumed to function independently. We demonstrate that this is not the case. Significantly, Vps3 has an epistatic relationship with Pdr5, a major yeast multidrug transporter. Thus, a double pdr5, vps3 deletion mutant is no more multidrug sensitive than its isogenic single-mutant counterparts. Subcellular fractionation experiments and analysis of purified plasma membrane vesicles indicate, however, that a vps3 mutation does not affect the membrane-localization or ATPase activity of Pdr5 even though rhodamine 6G efflux is reduced significantly. This suggests that Vps3 and probably other members of the carboxypeptidase Y vacuolar protein–sorting pathway are required for relaying xenobiotic compounds to transporters in the membrane.
Starting Page	573
Ending Page	583
Page Count	11
File Format	PDF
ISSN	16174615
Journal	Molecular and General Genetics MGG
Volume Number	279
Issue Number	6
e-ISSN	16174623
Language	English
Publisher	Springer-Verlag
Publisher Date	2008-03-08
Publisher Place	Berlin/Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pdr5 Multidrug resistance Vacuolar-sorting proteins Vps3 Cycloheximide resistance Animal Genetics and Genomics Plant Genetics & Genomics Microbial Genetics and Genomics Biochemistry Cell Biology
Content Type	Text
Resource Type	Article
Subject	Genetics Medicine Molecular Biology

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Pdr5-mediated multidrug resistance requires the CPY-vacuolar sorting protein Vps3: are xenobiotic compounds routed from the vacuole to plasma membrane transporters for efflux?

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Pdr5-mediated multidrug resistance requires the CPY-vacuolar sorting protein Vps3: are xenobiotic compounds routed from the vacuole to plasma membrane transporters for efflux?