title: Cryptococcus neoformans Yap1 is required for normal fluconazole and oxidative stress resistance.
abstract: Cryptococcus neoformans is a pathogen that is the most common cause of fungal meningitis. As with most fungal pathogens, the most prevalent clinical antifungal used to treat Cryptococcosis is orally administered fluconazole. Resistance to this antifungal is an increasing concern in treatment of fungal disease in general. Our knowledge of the specific determinants involved in fluconazole resistance in Cryptococcus is limited. Here we report the identification of an important genetic determinant of fluconazole resistance in C. neoformans that encodes a basic region-leucine zipper transcription factor homologous to Saccharomyces cerevisiae Yap1. Expression of a codon-optimized form of the Cn YAP1 cDNA in S. cerevisiae complemented defects caused by loss of the endogenous S. cerevisiae YAP1 gene and activated transcription from a reporter gene construct. Mutant strains of C. neoformans lacking YAP1 were hypersensitive to a range of oxidative stress agents but importantly also to fluconazole. Loss of Yap1 homologues from other fungal pathogens like Candida albicans or Aspergillus fumigatus was previously found to cause oxidant hypersensitivity but had no detectable effect on fluconazole resistance. Our data provide evidence for a unique biological role of Yap1 in wild-type fluconazole resistance in C. neoformans.
authors.affiliation: Departments of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Sanjoy
authors.initials: S
authors.lastname: Paul
authors.affiliation: Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Doering
authors.affiliation: Departments of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA. Electronic address: scott-moye-rowley@uiowa.edu.
authors.forename: W Scott
authors.initials: WS
authors.lastname: Moye-Rowley
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D003453:Cryptococcosis / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000235:genetics*; D025141:Drug Resistance, Fungal / Q000235:genetics; D005260:Female; D015725:Fluconazole / Q000494:pharmacology*; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018384:Oxidative Stress; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D050976:Basic-Leucine Zipper Transcription Factors; D005656:Fungal Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C086677:YAP1 protein, S cerevisiae; D015725:Fluconazole
keywords: Cryptococcus neoformans; Fluconazole resistance; Heterologous expression; Saccharomyces cerevisiae; Yap1 transcription factor