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Role of ABC transporters in aureobasidin A resistance.

ABSTRACT: Aureobasidin A (AbA) has strong antifungal effects arising from an unusual mechanism. We show that AbA interacts with ATP-binding cassette (ABC) transporters in yeast and mammalian cells. We isolated a gene of Saccharomyces cerevisiae that conferred resistance to AbA when the gene was present in multiple copies. The gene was identical to YOR1/YRS1, which confers resistance to oligomycin, reveromycin, and organic anions, none of which have structures similar to that of AbA. We also isolated an aur3R recessive mutant of S. cerevisiae with increased resistance to AbA. Northern hybridization showed that the aur3R mutant expressed not only YOR1 but also the ABC transporter-encoding gene PDR5 at high levels. Genetic studies showed that the aur3R mutant had a mutation in the PDR1 gene, which encodes a transcriptional regulator of PDR5 and YOR1. Analysis of a yor1 disruptant of the aur3/pdr1 mutant showed that both the functional YOR1 gene and the mutation in PDR1 were necessary for AbA resistance. These results suggest that YOR1 is more important than PDR5 for AbA resistance. We found in Candida albicans a novel gene whose sequence was similar to the sequence of YOR1 in S. cerevisiae. The amino acid sequence of the C. albicans YOR1 homolog showed no significant similarity to the sequences of CDR1 and CDR2, which are ABC transporters of C. albicans. Furthermore, AbA inhibited the efflux of the anticancer agent vincristine through P glycoproteins in cancer cells with multidrug resistance.

SUBMITTER: Ogawa A

PROVIDER: S-EPMC105537 | biostudies-literature | 1998 Apr

REPOSITORIES: biostudies-literature

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Role of ABC transporters in aureobasidin A resistance.

Ogawa A A Hashida-Okado T T Endo M M Yoshioka H H Tsuruo T T Takesako K K Kato I I

Antimicrobial agents and chemotherapy 19980401 4

Aureobasidin A (AbA) has strong antifungal effects arising from an unusual mechanism. We show that AbA interacts with ATP-binding cassette (ABC) transporters in yeast and mammalian cells. We isolated a gene of Saccharomyces cerevisiae that conferred resistance to AbA when the gene was present in multiple copies. The gene was identical to YOR1/YRS1, which confers resistance to oligomycin, reveromycin, and organic anions, none of which have structures similar to that of AbA. We also isolated an au ...[more]

PMID: 9559778

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Project description:Atherosclerosis, driven by inflamed lipid-laden lesions, can occlude the coronary arteries and lead to myocardial infarction. This chronic disease is a major and expensive health burden. However, the body is able to mobilize and excrete cholesterol and other lipids, thus preventing atherosclerosis by a process termed reverse cholesterol transport (RCT). Insight into the mechanism of RCT has been gained by the study of two rare syndromes caused by the mutation of ABC transporter loci. In Tangier disease, loss of ABCA1 prevents cells from exporting cholesterol and phospholipid, thus resulting in the build-up of cholesterol in the peripheral tissues and a loss of circulating HDL. Consistent with HDL being an athero-protective particle, Tangier patients are more prone to develop atherosclerosis. Likewise, sitosterolemia is another inherited syndrome associated with premature atherosclerosis. Here mutations in either the ABCG5 or G8 loci, prevents hepatocytes and enterocytes from excreting cholesterol and plant sterols, including sitosterol, into the bile and intestinal lumen. Thus, ABCG5 and G8, which from a heterodimer, constitute a transporter that excretes cholesterol and dietary sterols back into the gut, while ABCA1 functions to export excess cell cholesterol and phospholipid during the biogenesis of HDL. Interestingly, a third protein, ABCG1, that has been shown to have anti-atherosclerotic activity in mice, may also act to transfer cholesterol to mature HDL particles. Here we review the relationship between the lipid transport activities of these proteins and their anti-atherosclerotic effect, particularly how they may reduce inflammatory signaling pathways. Of particular interest are recent reports that indicate both ABCA1 and ABCG1 modulate cell surface cholesterol levels and inhibit its partitioning into lipid rafts. Given lipid rafts may provide platforms for innate immune receptors to respond to inflammatory signals, it follows that loss of ABCA1 and ABCG1 by increasing raft content will increase signaling through these receptors, as has been experimentally demonstrated. Moreover, additional reports indicate ABCA1, and possibly SR-BI, another HDL receptor, may directly act as anti-inflammatory receptors independent of their lipid transport activities. Finally, we give an update on the progress and pitfalls of therapeutic approaches that seek to stimulate the flux of lipids through the RCT pathway.

Dataset Information

Role of ABC transporters in aureobasidin A resistance.

Publications

Role of ABC transporters in aureobasidin A resistance.

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