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Transcriptional regulation of xenobiotic detoxification in Drosophila.

ABSTRACT: Living organisms, from bacteria to humans, display a coordinated transcriptional response to xenobiotic exposure, inducing enzymes and transporters that facilitate detoxification. Several transcription factors have been identified in vertebrates that contribute to this regulatory response. In contrast, little is known about this pathway in insects. Here we show that the Drosophila Nrf2 (NF-E2-related factor 2) ortholog CncC (cap 'n' collar isoform-C) is a central regulator of xenobiotic detoxification responses. A binding site for CncC and its heterodimer partner Maf (muscle aponeurosis fibromatosis) is sufficient and necessary for robust transcriptional responses to three xenobiotic compounds: phenobarbital (PB), chlorpromazine, and caffeine. Genetic manipulations that alter the levels of CncC or its negative regulator, Keap1 (Kelch-like ECH-associated protein 1), lead to predictable changes in xenobiotic-inducible gene expression. Transcriptional profiling studies reveal that more than half of the genes regulated by PB are also controlled by CncC. Consistent with these effects on detoxification gene expression, activation of the CncC/Keap1 pathway in Drosophila is sufficient to confer resistance to the lethal effects of the pesticide malathion. These studies establish a molecular mechanism for the regulation of xenobiotic detoxification in Drosophila and have implications for controlling insect populations and the spread of insect-borne human diseases.

SUBMITTER: Misra JR

PROVIDER: S-EPMC3175716 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Transcriptional regulation of xenobiotic detoxification in Drosophila.

Misra Jyoti R JR Horner Michael A MA Lam Geanette G Thummel Carl S CS

Genes & development 20110901 17

Living organisms, from bacteria to humans, display a coordinated transcriptional response to xenobiotic exposure, inducing enzymes and transporters that facilitate detoxification. Several transcription factors have been identified in vertebrates that contribute to this regulatory response. In contrast, little is known about this pathway in insects. Here we show that the Drosophila Nrf2 (NF-E2-related factor 2) ortholog CncC (cap 'n' collar isoform-C) is a central regulator of xenobiotic detoxifi ...[more]

PMID: 21896655

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Project description:Fungi are known to utilize transcriptional regulation of genes that encode efflux transporters to detoxify xenobiotics; however, to date it is unknown how fungi transcriptionally regulate and coordinate different phases of detoxification system (phase I, modification; phase II, conjugation; and phase III, secretion). Here we present evidence of an evolutionary convergence between the fungal and mammalian lineages, whereby xenobiotic detoxification genes (phase I coding for cytochrome P450 monooxygenases [CYP450s] and phase III coding for ATP-binding cassette [ABC] efflux transporters) are transcriptionally regulated by structurally unrelated proteins. Following next-generation RNA sequencing (RNA-seq) analyses of a filamentous fungus, Sclerotinia homoeocarpa, the causal agent of dollar spot on turfgrasses, a multidrug resistant (MDR) field strain was found to overexpress phase I and III genes, coding for CYP450s and ABC transporters for xenobiotic detoxification. Furthermore, there was confirmation of a gain-of-function mutation of the fungus-specific transcription factor S. homoeocarpa XDR1 (ShXDR1), which is responsible for constitutive and induced overexpression of the phase I and III genes, resulting in resistance to multiple classes of fungicidal chemicals. This fungal pathogen detoxifies xenobiotics through coordinated transcriptional control of CYP450s, biotransforming xenobiotics with different substrate specificities and ABC transporters, excreting a broad spectrum of xenobiotics or biotransformed metabolites. A Botrytis cinerea strain harboring the mutated ShXDR1 showed increased expression of phase I (BcCYP65) and III (BcatrD) genes, resulting in resistance to fungicides. This indicates the regulatory system is conserved in filamentous fungi. This molecular genetic mechanism for xenobiotic detoxification in fungi holds potential for facilitating discovery of new antifungal drugs and further studies of convergent and divergent evolution of xenobiotic detoxification in eukaryote lineages.IMPORTANCE Emerging multidrug resistance (MDR) in pathogenic filamentous fungi is a significant threat to human health and agricultural production. Understanding mechanisms of MDR is essential to combating fungal pathogens; however, there is still limited information on MDR mechanisms conferred by xenobiotic detoxification. Here, we report for the first time that overexpression of phase I drug-metabolizing monooxygenases (cytochrome P450s) and phase III ATP-binding cassette efflux transporters is regulated by a gain-of-function mutation in the fungus-specific transcription factor in the MDR strains of the filamentous plant-pathogenic fungus Sclerotinia homoeocarpa This study establishes a novel molecular mechanism of MDR through the xenobiotic detoxification pathway in filamentous fungi, which may facilitate the discovery of new antifungal drugs to control pathogenic fungi.

Project description:Hydrogen peroxide (H2O2) and nitric oxide (NO·) are toxic metabolites that immune cells use to attack pathogens. These antimicrobials can be present at the same time in phagosomes, and it remains unclear how bacteria deal with these insults when simultaneously present. Here, using Escherichia coli, we observed that simultaneous exposure to H2O2 and NO· leads to prioritized detoxification, where enzymatic removal of NO· is impeded until H2O2 has been eliminated. This phenomenon is reminiscent of carbon catabolite repression (CCR), where preferred carbon sources are catabolized prior to less desirable substrates; however, H2O2 and NO· are toxic, growth-inhibitory compounds rather than growth-promoting nutrients. To understand how NO· detoxification is delayed by H2O2 whereas H2O2 detoxification proceeds unimpeded, we confirmed that the effect depended on Hmp, which is the main NO· detoxification enzyme, and used an approach that integrated computational modeling and experimentation to delineate and test potential mechanisms. Plausible interactions included H2O2-dependent inhibition of hmp transcription and translation, direct inhibition of Hmp catalysis, and competition for reducing equivalents between Hmp and H2O2-degrading enzymes. Experiments illustrated that Hmp catalysis and NAD(P)H supply were not impaired by H2O2, whereas hmp transcription and translation were diminished. A dependence of this phenomenon on transcriptional regulation parallels CCR, and we found it to involve the transcriptional repressor NsrR. Collectively, these data suggest that bacterial regulation of growth inhibitor detoxification has similarities to the regulation of growth substrate consumption, which could have ramifications for infectious disease, bioremediation, and biocatalysis from inhibitor-containing feedstocks.IMPORTANCE Bacteria can be exposed to H2O2 and NO· concurrently within phagosomes. In such multistress situations, bacteria could have evolved to simultaneously degrade both toxic metabolites or preferentially detoxify one over the other. Here, we found that simultaneous exposure to H2O2 and NO· leads to prioritized detoxification, where detoxification of NO· is hampered until H2O2 has been eliminated. This phenomenon resembles CCR, where bacteria consume one substrate over others in carbon source mixtures. Further experimentation revealed a central role for transcriptional regulation in the prioritization of H2O2 over NO·, which is also important to CCR. This study suggests that regulatory scenarios observed in bacterial consumption of growth-promoting compound mixtures can be conserved in bacterial detoxification of toxic metabolite mixtures.

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Transcriptional regulation of xenobiotic detoxification in Drosophila.

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Transcriptional regulation of xenobiotic detoxification in Drosophila.

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