Journal article
Negative regulation of Candida glabrata Pdr1 by the deubiquitinase subunit Bre5 occurs in a ubiquitin independent manner
Molecular microbiology, Vol.110(2), pp.309-323
10/01/2018
DOI: 10.1111/mmi.14109
PMCID: PMC6348483
PMID: 30137659
Abstract
The primary route for development of azole resistance in the fungal pathogen Candida glabrata is acquisition of a point mutation in the PDR1 gene. This locus encodes a transcription factor that upon mutation drives high level expression of a range of genes including the ATP-binding cassette transporter-encoding gene CDR1. Pdr1 activity is also elevated in cells that lack the mitochondrial genome ((degrees) cells), with associated high expression of CDR1 driving azole resistance. To gain insight into the mechanisms controlling activity of Pdr1, we expressed a tandem affinity purification (TAP)-tagged form of Pdr1 in both wild-type ((+)) and (degrees) cells. Purified proteins were analyzed by multidimensional protein identification technology mass spectrometry identifying a protein called Bre5 as a factor that co-purified with TAP-Pdr1. In Saccharomyces cerevisiae, Bre5 is part of a deubiquitinase complex formed by association with the ubiquitin-specific protease Ubp3. Genetic analyses in C. glabrata revealed that loss of BRE5, but not UBP3, led to an increase in expression of PDR1 and CDR1 at the transcriptional level. These studies support the view that Bre5 acts as a negative regulator of Pdr1 transcriptional activity and behaves as a C. glabrata-specific modulator of azole resistance.
Details
- Title: Subtitle
- Negative regulation of Candida glabrata Pdr1 by the deubiquitinase subunit Bre5 occurs in a ubiquitin independent manner
- Creators
- Sanjoy Paul - Roy J. and Lucille A. Carver College of MedicineW. Hayes McDonald - Vanderbilt University Medical CenterW. Scott Moye-Rowley - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- Molecular microbiology, Vol.110(2), pp.309-323
- DOI
- 10.1111/mmi.14109
- PMID
- 30137659
- PMCID
- PMC6348483
- NLM abbreviation
- Mol Microbiol
- ISSN
- 0950-382X
- eISSN
- 1365-2958
- Publisher
- Wiley
- Number of pages
- 15
- Grant note
- R01GM049825 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) P30CA086862 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 10/01/2018
- Academic Unit
- Molecular Physiology and Biophysics; Internal Medicine
- Record Identifier
- 9984297611702771
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