Functional information from clinically-derived drug resistant forms of the Candida glabrata Pdr1 transcription factor

Lucia Simonicova; W Scott Moye-Rowley

doi:10.1371/journal.pgen.1009005

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Functional information from clinically-derived drug resistant forms of the Candida glabrata Pdr1 transcription factor

Journal article

Open access

Peer reviewed

Functional information from clinically-derived drug resistant forms of the Candida glabrata Pdr1 transcription factor

Lucia Simonicova and W Scott Moye-Rowley

PLoS genetics, Vol.16(8), pp.e1009005-e1009005

08/2020

DOI: 10.1371/journal.pgen.1009005

PMCID: PMC7473514

PMID: 32841236

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Abstract

Azole drugs are the most frequently used antifungal agents. The pathogenic yeast Candida glabrata acquires resistance to azole drugs via single amino acid substitution mutations eliciting a gain-of-function (GOF) hyperactive phenotype in the Pdr1 transcription factor. These GOF mutants constitutively drive high transcription of target genes such as the ATP-binding cassette transporter-encoding CDR1 locus. Previous characterization of Pdr1 has demonstrated that this factor is negatively controlled by the action of a central regulatory domain (CRD) of ~700 amino acids, in which GOF mutations are often found. Our earlier experiments demonstrated that a Pdr1 derivative in which the CRD was deleted gave rise to a transcriptional regulator that could not be maintained as the sole copy of PDR1 in the cell owing to its toxically high activity. Using a set of GOF PDR1 alleles from azole-resistant clinical isolates, we have analyzed the mechanisms acting to repress Pdr1 transcriptional activity. Our data support the view that Pdr1-dependent transactivation is mediated by a complex network of transcriptional coactivators interacting with the extreme C-terminal part of Pdr1. These coactivators include but are not limited to the Mediator component Med15A. Activity of this C-terminal domain is controlled by the CRD and requires multiple regions across the C-terminus for normal function. We also provide genetic evidence for an element within the transactivation domain that mediates the interaction of Pdr1 with coactivators on one hand while restricting Pdr1 activity on the other hand. These data indicate that GOF mutations in PDR1 block nonidentical negative inputs that would otherwise restrain Pdr1 transcriptional activation. The strong C-terminal transactivation domain of Pdr1 uses multiple different protein regions to recruit coactivators.

Antifungal Agents - adverse effects

Antifungal Agents - pharmacology

Azoles - adverse effects

Azoles - pharmacology

Candida glabrata - drug effects

Candida glabrata - genetics

Candida glabrata - pathogenicity

Candidiasis - drug therapy

Candidiasis - genetics

Candidiasis - microbiology

DNA-Binding Proteins

Drug Resistance, Fungal - drug effects

Drug Resistance, Fungal - genetics

Fungal Proteins - genetics

Gene Expression Regulation, Fungal - drug effects

Humans

Transcriptional Activation - drug effects

Details

Title: Subtitle: Functional information from clinically-derived drug resistant forms of the Candida glabrata Pdr1 transcription factor
Creators: Lucia Simonicova - University of Iowa, Molecular Physiology and Biophysics
W Scott Moye-Rowley - University of Iowa, Molecular Physiology and Biophysics
Resource Type: Journal article
Publication Details: PLoS genetics, Vol.16(8), pp.e1009005-e1009005
DOI: 10.1371/journal.pgen.1009005
PMID: 32841236
PMCID: PMC7473514
NLM abbreviation: PLoS Genet
ISSN: 1553-7390
eISSN: 1553-7404
Grant note: R01 GM049825 / NIGMS NIH HHS R01 AI152494 / NIAID NIH HHS
Language: English
Date published: 08/2020
Academic Unit: Molecular Physiology and Biophysics; Internal Medicine
Record Identifier: 9984228050802771

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