Regulating resistance: CncC:Maf, antioxidant response elements and the overexpression of detoxification genes in insecticide resistance

Abstract

Although genetic and genomic tools have greatly furthered our understanding of resistance-associated mutations in molecular target sites of insecticides, the genomic basis of transcriptional regulation of detoxification loci in insect pests and vectors remains relatively unexplored. Recent work using RNAi, reporter assays and comparative genomics are beginning to reveal the molecular architecture of this response, identifying critical transcription factors and their binding sites. Central to this is the insect ortholog of the mammalian transcription factor Nrf2, Cap 'n' Collar isoform-C (CncC) which as a heterodimer with Maf-S regulates the transcription of phase I, II and III detoxification loci in a range of insects, with CncC knockdown or upregulation directly affecting phenotypic resistance. CncC:Maf binds to specific antioxidant response element sequences upstream of detoxification genes to initiate transcription. Recent work is now identifying these binding sites for resistance-associated loci and, coupled with genome sequence data and reporter assays, enabling identification of polymorphisms in the CncC:Maf binding site which regulate the insecticide resistance phenotype.

Transcription factors CncC/Maf and AhR/ARNT coordinately regulate the expression of multiple GSTs conferring resistance to chlorpyrifos and cypermethrin in Spodoptera exigua

“…CncC and Maf are key transcription factors mediating xenobiotic and oxidative responses in animals and also involved in the regulation of insect development . CncC knockdown by RNAi impacts the expression of hundreds of genes including detoxifying genes of phase I, II and III detoxification . Over‐production of CncC and Maf will give rise to wide influences on gene expression, especially enhancing the expression of multiple detoxification genes under the control of CncC/Maf binding element .…”

“…This regulatory element is the key antioxidant response and XRE in animals. CncC, the insect ortholog of mammalian transcription factor Nrf2, as a heterodimer with Maf (muscle aponeurosis fibromatosis) regulates the transcription of diverse antioxidant and detoxifying genes in a range of arthropods, and has been found to regulate the expression of resistance‐associated P450s in T. castanuem , Aphis gossypii , A. gambiae , D. melanogaster and mite ( Tetranychus cinnabarinus ) . The expression of many detoxification genes is under the control of this cis ‐regulatory element in insects …”

“…Therefore, this cis ‐regulatory element is involved in the expression regulation of these three SeGSTs in S. exigua . However, the transcriptional activation of target genes under the control of this regulatory element needs to recruit CncC and Maf, and the expression levels of these two transcription factors also influence the transcription activities of target genes . The expression inhibition of CncC by RNAi of dsRNA can result in the expression decline of target genes, including the genes involved in all three phases of insecticide detoxification .…”

Cisandtrans-acting variants contribute to survivorship in a naïveDrosophila melanogasterpopulation exposed to ryanoid insecticides

“…These genes have previously been found to be regulated by cnc (35), a transcription factor well conserved across both vertebrates and invertebrates (39). cnc and its mammalian homolog Nrf2 are CNC-bZIP transcription factors that play a well-conserved role in oxidative stress response (40). While most studies characterize this pathway in terms of its induction in response to oxidative stress, the transcript-level variation identified in this study comes from unexposed flies, suggesting variation in the constitutive expression level of cnc-regulated transcripts among DGRP lines, a phenomenon that has previously been linked to insecticide resistance (35, 40).…”

Transcriptomic analysis of insecticide resistance in the lymphatic filariasis vectorCulex quinquefasciatus

“…Metabolic resistance, which involves the over-expression, or increased catalytic capability of metabolic enzymes, is a less tractable mechanism since members of diverse gene families including carboxy/cholinesterases, glutathione S-transferases (GSTs) and cytochrome P450 monooxygenases (P450s) have previously been associated with resistance to different classes of insecticide in a range of vector species 17–19 . Over-expression of detoxification genes can be triggered by a range of mechanisms including gene duplication 20 , as observed for the resistance to organophosphates in C. quinquefasciatus mediated by esterases 21 , cis -regulatory elements 22,23 , trans -regulatory elements, or changes in post-transcriptional repression due to differential expression of miRNAs 24 .…”