ABC proteins in yeast and fungal pathogens

Abstract

All fungal genomes harbour numerous ABC (ATP-binding cassette) proteins located in various cellular compartments such as the plasma membrane, vacuoles, peroxisomes and mitochondria. Most of them have initially been discovered through their ability to confer resistance to a multitude of drugs, a phenomenon called PDR (pleiotropic drug resistance) or MDR (multidrug resistance). Studying the mechanisms underlying PDR/MDR in yeast is of importance in two ways: first, ABC proteins can confer drug resistance on pathogenic fungi such as Candida spp., Aspergillus spp. or Cryptococcus neoformans; secondly, the well-established genetic, biochemical and cell biological tractability of Saccharomyces cerevisiae makes it an ideal tool to study basic mechanisms of drug transport by ABC proteins. In the past, knowledge from yeast has complemented work on human ABC transporters involved in anticancer drug resistance or genetic diseases. Interestingly, increasing evidence available from yeast and other organisms suggests that ABC proteins play a physiological role in membrane homoeostasis and lipid distribution, although this is being intensely debated in the literature.

Mitochondria Influence CDR1 Efflux Pump Activity, Hog1-Mediated Oxidative Stress Pathway, Iron Homeostasis, and Ergosterol Levels in Candida albicans

“…Previous studies with S. cerevisiae and C. glabrata indicate that loss of mitochondrial function leads to an elevated expression of the ABC transporter genes (ScPDR5, CgCDR1, and CgCDR2) via transcription factors ScPdr3 and CgPdr1, causing the multidrug resistance (MDR) phenotype (39,40,73,74). Here, we show that in C. albicans, whereas aberrant mitochondria, modestly affects susceptibility to fluconazole, there is a significant reduction in MIC 80 values for ketoconazole and itraconazole (Table 4).…”

Differential Contributions of Five ABC Transporters to Mutidrug Resistance, Antioxidion and Virulence of Beauveria bassiana, an Entomopathogenic Fungus

“…2), which were used in MDR assays due to differences in structure and function. Apparently, ABC pump-dependent MDR mechanisms exist in entomopathogenic fungi as do in yeasts and human and plant pathogenic fungi [13], [16].…”

“…As a large family, ABC transporter proteins can energize the transport of a huge variety of compounds across biological membranes through ATP hydrolysis and confer cellular resistance to a broad spectrum of drug substrates [i.e., MDR or PDR (pleiotropic drug resistance) phenomenon] or a very limited number of substrates [13]. They are structurally featured with essential nucleotide-binding domain(s) (NBD) and one or two hydrophobic transmembrane domains (TMDs) and usually composed of six K-helical transmembrane segments (TMSs), forming the domain architectures of full-size [(TMS 6 −NBD) 2 or (NBD−TMS 6 ) 2 ], half-size (TMS 6 −NBD) and TMD-lacking (NBD or NBD 2 ) transporters [14].…”

Functional analysis of an ATP-binding cassette transporter protein from Aspergillus fumigatus by heterologous expression in Saccharomyces cerevisiae

“…These proteins have been extensively studied in other fungal pathogens, especially in Candida albicans and Candida glabrata , where azole resistance occurs as a result of the overexpression of particular ABC transporter proteins (Morschhauser, 2010; Shahi and Moye-Rowley, 2009; Klein et al, 2011; Prasad and Goffeau, 2012). One of the most important of these Candida ABC transporters is the Cdr1 protein, first discovered on the basis of its ability to complement the drug sensitive phenotype of a pdr5Δ strain of S. cerevisiae (Prasad et al, 1995).…”