A nuclear receptor-like pathway regulating multidrug resistance in fungi.
Multidrug resistance (MDR) is a serious complication during treatment of opportunistic fungal infections that frequently afflict immunocompromised individuals, such as transplant recipients and cancer patients undergoing cytotoxic chemotherapy. Improved knowledge of the molecular pathways controlling MDR in pathogenic fungi should facilitate the development of novel therapies to combat these intransigent infections. MDR is often caused by upregulation of drug efflux pumps by members of the fungal zinc-cluster transcription-factor family (for example Pdr1p orthologues). However, the molecular mechanisms are poorly understood. Here we show that Pdr1p family members in Saccharomyces cerevisiae and the human pathogen Candida glabrata directly bind to structurally diverse drugs and xenobiotics, resulting in stimulated expression of drug efflux pumps and induction of MDR. Notably, this is mechanistically similar to regulation of MDR in vertebrates by the PXR nuclear receptor, revealing an unexpected functional analogy of fungal and metazoan regulators of MDR. We have also uncovered a critical and specific role of the Gal11p/MED15 subunit of the Mediator co-activator and its activator-targeted KIX domain in antifungal/xenobiotic-dependent regulation of MDR. This detailed mechanistic understanding of a fungal nuclear receptor-like gene regulatory pathway provides novel therapeutic targets for the treatment of multidrug-resistant fungal infections.
Thakur
Jitendra K
JK
Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA.
Arthanari
Haribabu
H
Yang
Fajun
F
Pan
Shih-Jung
SJ
Fan
Xiaochun
X
Breger
Julia
J
Frueh
Dominique P
DP
Gulshan
Kailash
K
Li
Darrick K
DK
Mylonakis
Eleftherios
E
Struhl
Kevin
K
Moye-Rowley
W Scott
WS
Cormack
Brendan P
BP
Wagner
Gerhard
G
Näär
Anders M
AM
D000818:Animals; D000935:Antifungal Agents / Q000378:metabolism / Q000494:pharmacology; D041221:Candida glabrata / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000235:genetics; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal / Q000235:genetics; D005800:Genes, Fungal / Q000235:genetics; D056892:Mediator Complex; D005810:Multigene Family; D000077297:Pregnane X Receptor; D017434:Protein Structure, Tertiary; D011987:Receptors, Steroid / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D015262:Xenobiotics / Q000378:metabolism
D000935:Antifungal Agents; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C058337:GAL11 protein, S cerevisiae; D056892:Mediator Complex; C085480:PDR1 protein, S cerevisiae; C089261:PDR3 protein, S cerevisiae; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D015262:Xenobiotics