A Hyperactive Form of the Zinc Cluster Transcription Factor Stb5 Causes YOR1 Overexpression and Beauvericin Resistance in Candida albicans

Abstract

Gain-of-function mutations in the zinc cluster transcription factors Mrr1, Tac1, and Upc2, which result in constitutive overexpression of their target genes, are a frequent cause of fluconazole resistance in the pathogenic yeast In this study, we show that an activated form of another zinc cluster transcription factor, Stb5, confers resistance to the natural compound beauvericin via the overexpression of, encoding an efflux pump of the ATP-binding cassette transporter superfamily. Beauvericin was recently shown to potentiate the activity of azole drugs against Although Yor1 did not contribute to fluconazole resistance when cells were treated with the drug alone, Stb5-mediated overexpression diminished the synergistic effect of the fluconazole-beauvericin combination, thereby enhancing fluconazole resistance in beauvericin-treated cells. Stb5-mediated overexpression also suppressed the inhibition of hyphal growth, an important virulence trait of, by beauvericin. Therefore, activating mutations in Stb5, which result in constitutive overexpression, may enable to acquire resistance to beauvericin and thereby overcome both the sensitization to azole drugs and the inhibition of morphogenesis caused by this compound.

Availability of Zinc Impacts Interactions between Streptococcus sanguinis and Pseudomonas aeruginosa in Coculture

“…Zinc is an essential micronutrient for all organisms, serves as a structural or catalytic cofactor in 5 to 6% of proteins in the bacterial proteome (22)(23)(24), and can play an important role in the expression of key virulence factors (25)(26)(27)(28)(29)(30)(31)(32). However, high concentrations of zinc are toxic, possibly due to competition with other relevant metal ions (24,33), inhibition of key enzymes and essential metabolic reactions in the cell (32,34,35), and/or induction of membrane stress (36).…”

Unravel the regulatory mechanism of Yrr1p phosphorylation in response to vanillin stress in Saccharomyces cerevisiae

“…5c), indicating that the dephosphorylated mutations at positions 134 and 185 likely caused Yrr1p to be anchored in the nucleus and continuously activate the expression of SNQ2 and YOR1 in the absence of vanillin. SNQ2 and YOR1, encoding ABC transporters, was reported participate in the efflux of many drugs [33,34]. Our previous work also proved that the overexpression of these two genes can shorten the delay period and improve the vanillin tolerance of S. cerevisiae [26].…”

Unmasking of CgYor1-Dependent Azole Resistance Mediated by Target of Rapamycin (TOR) and Calcineurin Signaling in Candida glabrata

“…In both S. cerevisiae and C. albicans , Yor1 is known to transport organic anions, especially the macrolide oligomycin (OMY) ( 32 , 33 ). A cyclic hexadepsipeptide natural product beauvericin (BEA) is another reported substrate of ScYor1 and CaYor1 ( 34 , 35 ).…”