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A C. elegans orphan nuclear receptor contributes to xenobiotic resistance
T H Lindblom1, G J Pierce, A E Sluder
1Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA.
Abstract:
Lipophilic endocrine signals in metazoans, including the steroid, thyroid, and retinoid hormones, alter gene expression in target cells by binding to and modulating the activity of nuclear receptor (NR) transcription factors [1]. In vertebrates, xenobiotic and pharmacologic compounds can regulate the expression of protective metabolic enzymes via specific "xenobiotic sensing" NRs [2-4]. Here, we report evidence suggesting that this activity is an ancient conserved function for the NR class containing these receptors. Specifically, we show that a Caenorhabditis elegans member of this NR class, nhr-8, is required for wild-type levels of resistance to the toxins colchicine and chloroquine. The nhr-8 promoter is active in the nematode gut, a tissue that also expresses the ABC transporter, PGP-3, which contributes to defense against these toxins [5]. In contrast to pgp-3 mutants, nhr-8 mutants are not more sensitive than wild-type to pyocyanin-dependent killing by the pathogenic bacterium Pseudomonas aeruginosa. We conclude that NHR-8 functions in the nematode xenobiotic defense system and that NHR-8 and PGP-3 have overlapping, but distinct, spectra of toxin specificity.
Insights
The nuclear receptor NHR-8 in C. elegans is crucial for defending against toxins like colchicine and chloroquine. This study reveals an ancient role for nuclear receptors in xenobiotic defense systems.
Area of Science:
- Molecular Biology
- Genetics
- Toxicology
Background:
- Lipophilic hormones (steroid, thyroid, retinoid) regulate gene expression via nuclear receptors (NRs).
- Vertebrate NRs sense xenobiotics, modulating protective metabolic enzymes.
- This xenobiotic sensing is hypothesized to be an ancient, conserved NR function.
Purpose of the Study:
- To investigate the ancient conserved function of NRs in xenobiotic defense.
- To determine the role of the Caenorhabditis elegans NR, nhr-8, in toxin resistance.
Main Methods:
- Utilized C. elegans as a model organism.
- Assessed toxin resistance in wild-type and nhr-8 mutant strains.
- Examined nhr-8 promoter activity in the nematode gut.
- Investigated the interaction with the ABC transporter PGP-3 and Pseudomonas aeruginosa.
Main Results:
- nhr-8 mutants exhibit reduced resistance to colchicine and chloroquine.
- nhr-8 is expressed in the nematode gut, a site of xenobiotic defense.
- nhr-8 and PGP-3 show overlapping but distinct toxin specificities.
- nhr-8 mutants are not more susceptible to Pseudomonas aeruginosa infection.
Conclusions:
- NHR-8 functions within the nematode xenobiotic defense system.
- This highlights an ancient, conserved role for NRs in detoxification pathways.
- NHR-8 and PGP-3 represent distinct but complementary defense mechanisms against toxins.