Conserved and Unique Roles of bHLH-PAS Transcription Factors in Insects – From Clock to Hormone Reception

Tumova, Sarka; Dolezel, David; Jindra, Marek

doi:10.1016/j.jmb.2023.168332

Cited by 7 publications

(7 citation statements)

References 279 publications

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“…55 Since juvenoids directly target insect hormonal regulation, these insecticides are EDCs by nature and may cause environmental harm by affecting diverse non-target invertebrate species to which JH signaling is vital. 33–36 On the other hand, juvenoids are potentially beneficial as they, in theory, should not affect vertebrates that evolutionarily lack the MET/GCE JHR proteins, 8 the primary target of both native JHs and juvenoids. 26…”

Section: Discussionmentioning

confidence: 99%

“…9 To form a transcriptionally active, DNA-binding JHR complex, GCE (or MET) dimerizes with another bHLH-PAS protein called taiman (TAI), 4,13,14 an insect ortholog of the mammalian nuclear receptor coactivator (NCoA) proteins. 8 Binding of JH or another agonist to GCE/MET induces its nuclear import, 15 dissociation from a chaperone complex with HSP90 16,17 and the ensuing interaction with TAI. 13,14,[16][17][18][19] The GCE:TAI or MET:TAI heterodimer binds DNA JH-response elements (JHREs) and initiates transcription of target genes.…”

Section: Introductionmentioning

confidence: 99%

“…5,8 Although not orthologous, both proteins share a similar architecture of functional domains including regions bound by HSP90 in the absence of agonists, and regions mediating dimerization with bHLH-PAS partners when agonists bind to the cognate PAS-B cavities. 8,20,21 One difference is that GCE/MET pairs with TAI, whereas AHR forms a heterodimer with the AHR nuclear translocator (ARNT) that is only remotely related to NCoA. 8 The most striking common feature of AHR [22][23][24] and GCE/MET 9,25,26 is that both proteins can be activated by chemically diverse, low-molecular weight ligands.…”

Section: Introductionmentioning

confidence: 99%

“…8,20,21 One difference is that GCE/MET pairs with TAI, whereas AHR forms a heterodimer with the AHR nuclear translocator (ARNT) that is only remotely related to NCoA. 8 The most striking common feature of AHR [22][23][24] and GCE/MET 9,25,26 is that both proteins can be activated by chemically diverse, low-molecular weight ligands. AHR agonists range from environmental toxins including polycyclic aromatic hydrocarbons (PAHs) and PAH-like chemicals such as bnaphthoflavone (b-NF), products of tryptophan degradation (e.g., 6-formylindolo [3,2-b]carbazole; FICZ) to metabolites of the intestinal microflora such as indirubin [22][23][24] .…”

Section: Introductionmentioning

confidence: 99%

“…8,20,21 One difference is that GCE/MET pairs with TAI, whereas AHR forms a heterodimer with the AHR nuclear translocator (ARNT) that is only remotely related to NCoA. 8…”

Section: Introductionmentioning

confidence: 99%

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Unique and Common Agonists Activate the Insect Juvenile Hormone Receptor and the Human AHR

Sedlak,

Tuma,

Kolla

et al. 2024

Preprint

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Transcription factors of the bHLH-PAS family play vital roles in animal development, physiology, and disease. Two members of the family require binding of low-molecular weight ligands for their activity: the vertebrate aryl hydrocarbon receptor (AHR) and the insect juvenile hormone receptor (JHR). In the fly Drosophila melanogaster, the paralogous proteins GCE and MET constitute the ligand-binding component of JHR complexes. Whilst GCE/MET and AHR are phylogenetically heterologous, their mode of action is similar. JHR is targeted by several synthetic agonists that serve as insecticides disrupting the insect endocrine system. AHR is an important regulator of human endocrine homeostasis and it responds to environmental pollutants and endocrine disruptors. Whether AHR signaling is affected by compounds that can activate JHR has not been reported. To address this question, we screened a chemical library of 50,000 compounds to identify 93 novel JHR agonists in a reporter system based on Drosophila cells. Of these compounds, 26% modulated AHR signaling in an analogous reporter assay in a human cell line, indicating a significant overlap in the agonist repertoires of the two receptors. To explore the structural features of agonist-dependent activation of JHR and AHR, we compared the ligand-binding cavities and their interactions with selective and common ligands of AHR and GCE. Molecular dynamics modeling revealed ligand-specific as well as conserved side chains within the respective cavities. Significance of predicted interactions was supported through site-directed mutagenesis. The results have indicated that synthetic insect juvenile hormone agonists might interfere with AHR signaling in human cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…8,20,21 One difference is that GCE/MET pairs with TAI, whereas AHR forms a heterodimer with the AHR nuclear translocator (ARNT) that is only remotely related to NCoA. 8…”

Section: Introductionmentioning

confidence: 99%

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