Cryptococcus neoformans Yap1 is required for normal fluconazole and oxidative stress resistance

Sanjoy Paul; Tamara L Doering; W. Scott Moye-Rowley

doi:10.1016/j.fgb.2014.10.015

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Cryptococcus neoformans Yap1 is required for normal fluconazole and oxidative stress resistance

Journal article

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Cryptococcus neoformans Yap1 is required for normal fluconazole and oxidative stress resistance

Sanjoy Paul, Tamara L Doering and W. Scott Moye-Rowley

Fungal genetics and biology, Vol.74, pp.1-9

01/2015

DOI: 10.1016/j.fgb.2014.10.015

PMCID: PMC4293237

PMID: 25445311

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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 Cryptococcus 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 .

heterologous expression

Cryptococcus neoformans

Yap1 transcription factor

Saccharomyces cerevisiae

fluconazole resistance

Details

Title: Subtitle: Cryptococcus neoformans Yap1 is required for normal fluconazole and oxidative stress resistance
Creators: Sanjoy Paul - Departments of Molecular Physiology and Biophysics, Washington University School of Medicine, St. Louis, MO USA
Tamara L Doering - Carver College of Medicine, University of Iowa, Iowa City, IA USA and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO USA
W. Scott Moye-Rowley - Departments of Molecular Physiology and Biophysics, Washington University School of Medicine, St. Louis, MO USA
Resource Type: Journal article
Publication Details: Fungal genetics and biology, Vol.74, pp.1-9
DOI: 10.1016/j.fgb.2014.10.015
PMID: 25445311
PMCID: PMC4293237
NLM abbreviation: Fungal Genet Biol
ISSN: 1087-1845
eISSN: 1096-0937
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: GM49825
Language: English
Date published: 01/2015
Academic Unit: Molecular Physiology and Biophysics; Internal Medicine
Record Identifier: 9984025697802771

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