A nuclear receptor-like pathway regulating multidrug resistance in fungi

Jitendra K. Thakur, Haribabu Arthanari, Fajun Yang, Shih Jung Pan, Xiaochun Fan, Julia Breger, Dominique P Frueh, Kailash Gulshan, Darrick K. Li, Eleftherios Mylonakis, Kevin Struhl, W. Scott Moye-Rowley, Brendan P Cormack, Gerhard Wagner, Anders M. Näär

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)604-609
Number of pages6
JournalNature
Volume452
Issue number7187
DOIs
StatePublished - Apr 3 2008

Fingerprint

Multiple Drug Resistance
Cytoplasmic and Nuclear Receptors
Fungi
Mycoses
Xenobiotics
Pharmaceutical Preparations
Candida glabrata
Opportunistic Infections
Therapeutics
Regulator Genes
Saccharomyces cerevisiae
Vertebrates
Zinc
Transcription Factors
Up-Regulation
Drug Therapy
Infection
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Thakur, J. K., Arthanari, H., Yang, F., Pan, S. J., Fan, X., Breger, J., ... Näär, A. M. (2008). A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature, 452(7187), 604-609. https://doi.org/10.1038/nature06836

A nuclear receptor-like pathway regulating multidrug resistance in fungi. / Thakur, Jitendra K.; Arthanari, Haribabu; Yang, Fajun; Pan, Shih Jung; Fan, Xiaochun; Breger, Julia; Frueh, Dominique P; Gulshan, Kailash; Li, Darrick K.; Mylonakis, Eleftherios; Struhl, Kevin; Moye-Rowley, W. Scott; Cormack, Brendan P; Wagner, Gerhard; Näär, Anders M.

In: Nature, Vol. 452, No. 7187, 03.04.2008, p. 604-609.

Research output: Contribution to journalArticle

Thakur, JK, Arthanari, H, Yang, F, Pan, SJ, Fan, X, Breger, J, Frueh, DP, Gulshan, K, Li, DK, Mylonakis, E, Struhl, K, Moye-Rowley, WS, Cormack, BP, Wagner, G & Näär, AM 2008, 'A nuclear receptor-like pathway regulating multidrug resistance in fungi', Nature, vol. 452, no. 7187, pp. 604-609. https://doi.org/10.1038/nature06836
Thakur JK, Arthanari H, Yang F, Pan SJ, Fan X, Breger J et al. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature. 2008 Apr 3;452(7187):604-609. https://doi.org/10.1038/nature06836
Thakur, Jitendra K. ; Arthanari, Haribabu ; Yang, Fajun ; Pan, Shih Jung ; Fan, Xiaochun ; Breger, Julia ; Frueh, Dominique P ; Gulshan, Kailash ; Li, Darrick K. ; Mylonakis, Eleftherios ; Struhl, Kevin ; Moye-Rowley, W. Scott ; Cormack, Brendan P ; Wagner, Gerhard ; Näär, Anders M. / A nuclear receptor-like pathway regulating multidrug resistance in fungi. In: Nature. 2008 ; Vol. 452, No. 7187. pp. 604-609.
@article{adddb8613a1e47f0889f91fa193fd116,
title = "A nuclear receptor-like pathway regulating multidrug resistance in fungi",
abstract = "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.",
author = "Thakur, {Jitendra K.} and Haribabu Arthanari and Fajun Yang and Pan, {Shih Jung} and Xiaochun Fan and Julia Breger and Frueh, {Dominique P} and Kailash Gulshan and Li, {Darrick K.} and Eleftherios Mylonakis and Kevin Struhl and Moye-Rowley, {W. Scott} and Cormack, {Brendan P} and Gerhard Wagner and N{\"a}{\"a}r, {Anders M.}",
year = "2008",
month = "4",
day = "3",
doi = "10.1038/nature06836",
language = "English (US)",
volume = "452",
pages = "604--609",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7187",

}

TY - JOUR

T1 - A nuclear receptor-like pathway regulating multidrug resistance in fungi

AU - Thakur, Jitendra K.

AU - Arthanari, Haribabu

AU - Yang, Fajun

AU - Pan, Shih Jung

AU - Fan, Xiaochun

AU - Breger, Julia

AU - Frueh, Dominique P

AU - Gulshan, Kailash

AU - Li, Darrick K.

AU - Mylonakis, Eleftherios

AU - Struhl, Kevin

AU - Moye-Rowley, W. Scott

AU - Cormack, Brendan P

AU - Wagner, Gerhard

AU - Näär, Anders M.

PY - 2008/4/3

Y1 - 2008/4/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=41649118757&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41649118757&partnerID=8YFLogxK

U2 - 10.1038/nature06836

DO - 10.1038/nature06836

M3 - Article

C2 - 18385733

AN - SCOPUS:41649118757

VL - 452

SP - 604

EP - 609

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7187

ER -