A gain-of-function mutation in the transcription factor Upc2p causes upregulation of ergosterol biosynthesis genes and increased fluconazole resistance in a clinical Candida albicans isolate

Nico Dunkel, Teresa T. Liu, Katherine S. Barker, Ramin Homayouni, Joachim Morschhäuser, Phillip Rogers

Research output: Contribution to journalArticle

123 Citations (Scopus)

Abstract

In the pathogenic yeast Candida albicans, the zinc cluster transcription factor Upc2p has been shown to regulate the expression of ERG11 and other genes involved in ergosterol biosynthesis upon exposure to azole antifungals. ERG11 encodes lanosterol demethylase, the target enzyme of this antifungal class. Overexpression of UPC2 reduces azole susceptibility, whereas its disruption results in hypersusceptibility to azoles and reduced accumulation of exogenous sterols. Overexpression of ERG11 leads to the increased production of lanosterol demethylase, which contributes to azole resistance in clinical isolates of C. albicans, but the mechanism for this has yet to be determined. Using genome-wide gene expression profiling, we found UPC2 and other genes involved in ergosterol biosynthesis to be coordinately upregulated with ERG11 in a fluconazole-resistant clinical isolate compared with a matched susceptible isolate from the same patient. Sequence analysis of the UPC2 alleles of these isolates revealed that the resistant isolate contained a single-nucleotide substitution in one UPC2 allele that resulted in a G648D exchange in the encoded protein. Introduction of the mutated allele into a drug-susceptible strain resulted in constitutive upregulation of ERG11 and increased resistance to fluconazole. By comparing the gene expression profiles of the fluconazole-resistant isolate and of strains carrying wild-type and mutated UPC2 alleles, we identified target genes that are controlled by Upc2p. Here we show for the first time that a gain-of-function mutation in UPC2 leads to the increased expression of ERG11 and imparts resistance to fluconazole in clinical isolates of C. albicans.

Original languageEnglish (US)
Pages (from-to)1180-1190
Number of pages11
JournalEukaryotic Cell
Volume7
Issue number7
DOIs
StatePublished - Jul 1 2008

Fingerprint

Ergosterol
azoles
Azoles
fluconazole
Fluconazole
ergosterol
Candida albicans
Transcription Factors
Up-Regulation
transcription factors
Alleles
Lanosterol
biosynthesis
lanosterol
alleles
Mutation
Genes
genes
gene expression
Gene Expression Profiling

All Science Journal Classification (ASJC) codes

  • Agricultural and Biological Sciences(all)
  • Microbiology

Cite this

A gain-of-function mutation in the transcription factor Upc2p causes upregulation of ergosterol biosynthesis genes and increased fluconazole resistance in a clinical Candida albicans isolate. / Dunkel, Nico; Liu, Teresa T.; Barker, Katherine S.; Homayouni, Ramin; Morschhäuser, Joachim; Rogers, Phillip.

In: Eukaryotic Cell, Vol. 7, No. 7, 01.07.2008, p. 1180-1190.

Research output: Contribution to journalArticle

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