Abstract
BackgroundVertebrate glucocorticoid receptor (GR) is an evolutionary-conserved cortisol-regulated nuclear receptor that controls key metabolic and developmental pathways. Upon binding to cortisol, GR acts as an immunosuppressive transcription factor. Drosophila melanogaster, a model organism to study innate immunity, can also be immunosuppressed by glucocorticoids. However, while the genome of fruit fly harbors 18 nuclear receptor genes, the functional homolog of vertebrate GR has not been identified.ResultsIn this study, we demonstrated that while D. melanogaster is susceptible to Saccharomyces cerevisiae oral infection, the oral exposure to cortisol analogs, cortisone acetate or estrogen, increases fly sensitivity to yeast challenge. To understand the mechanism of this steroid-induced immunosuppression, we identified the closest genetic GR homolog as D. melanogaster Estrogen Related Receptor (ERR) gene. We discovered that Drosophila ERR is necessary for cortisone acetate- and estrogen-mediated increase in sensitivity to fungal infection: while ERR mutant flies are as sensitive to the fungal challenge as the wildtype flies, the yeast-sensitivity of ERR mutants is not increased by these steroids. Interestingly, the fungal cortisone analog, ergosterol, did not increase the susceptibility of Drosophila to yeast infection. The immunosuppressive effect of steroids on the sensitivity of flies to fungi is evolutionary conserved in insects, as we show that estrogen significantly increases the yeast-sensitivity of Culex quinquefasciatus mosquitoes, whose genome contains a close ortholog of the fly ERR gene.ConclusionsThis study identifies a D. melanogaster gene that structurally resembles vertebrate GR and is functionally necessary for the steroid-mediated immunosuppression to fungal infections.
Highlights
Vertebrate glucocorticoid receptor (GR) is an evolutionary-conserved cortisol-regulated nuclear receptor that controls key metabolic and developmental pathways
Human GR belongs to the nuclear receptor (NR) subfamily 3, which is comprised of a total of nine family members, such as Homo sapiens estrogen-related receptor and estrogen receptor
We aligned the sequence of D. melanogaster Estrogen Related Receptor (ERR) (dmERR) with sequences of several members of human NR subfamily 3 and observed an overall amino acid homology between 47 to 58% (Fig. 1b), with high similarity in the DNA binding domain (DBD) (70–96%) and the ligand binding domain (LBD) (55–57%) (Additional file 1)
Summary
Vertebrate glucocorticoid receptor (GR) is an evolutionary-conserved cortisol-regulated nuclear receptor that controls key metabolic and developmental pathways. NF-κB is evolutionary-conserved and an integral part of the fruit fly Drosophila melanogaster innate immune response when challenged with entomopathogenic microbes. The Imd pathway is primarily induced by gram-negative bacteria by recognizing DAP-type peptidoglycan via PGRPLC receptors located on the cell surface of enterocytes or fat body cells [5, 7]. The Toll pathway detects lysine-type peptidoglycan of gram-positive bacteria via PGRP-SA and GNBP1, as well as ß-glucans on the cell walls of fungi via GNBP3. This triggers the activation of the Toll receptor, and leads to the nuclear translocation of the NF-κB transcription factor Dif, activating the transcription of AMPs such as drosomycin [5] (Fig. 1a, right panel). Recent studies show that sensing of the type of the bacterial cell wall is less stringent than previously thought and that both fly pathways are capable of detecting lys- and dap-peptidoglycan based on the accessibility of bacterial cell wall [7]
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