A mammalian lysosomal membrane protein confers multidrug resistance upon expression in Saccharomyces cerevisiae

Mouse transporter protein (MTP) is a highly conserved polytopic membrane pr otein present in mammalian lysosomes and endosomes. The role of MTP in regu lating the in vivo subcellular distribution of numerous structurally distin ct small molecules has been examined in this study by its expression in a d rug-sensitive strain of the yeast Saccharomyces cerevisiae. Surprisingly, t he expression of MTP in membranes of an intracellular compartment resulted in a cellular resistance or hypersensitivity to a range of drugs that inclu ded nucleoside and nucleobase analogs, antibiotics, anthracyclines, ionopho res, and steroid hormones. The intracellular bioavailability of steroid hor mones was altered by MTP, as determined using an in vivo glucocorticoid rec eptor-driven reporter assay in yeast, suggesting that the MTP-regulated dru g sensitivity arose due to a change in the subcellular compartmentalization of steroid hormones and other drugs. MTP-regulated drug sensitivity in yea st was blocked to varying degrees by compounds that inhibit lysosomal funct ion, interfere with intracellular cholesterol transport, or modulate the mu ltidrug resistance phenotype of mammalian cells. These results indicate tha t MTP is involved in the subcellular compartmentalization of diverse hydrop hobic small molecules and contributes to the inherent drug sensitivity or r esistance of the mammalian cell.