Vertebrate 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. In 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. This study identifies a D. melanogaster gene that structurally resembles vertebrate GR and is functionally necessary for the steroid-mediated immunosuppression to fungal infections.

中文翻译：

---

果蝇糖皮质激素受体的鉴定。


脊椎动物糖皮质激素受体（GR）是一种进化保守的皮质醇调节核受体，控制关键的代谢和发育途径。与皮质醇结合后，GR 充当免疫抑制转录因子。黑腹果蝇是研究先天免疫的模型生物，糖皮质激素也可抑制其免疫。然而，虽然果蝇的基因组包含 18 个核受体基因，但脊椎动物 GR 的功能同源物尚未确定。在这项研究中，我们证明，虽然黑腹果蝇对酿酒酵母口腔感染敏感，但口服皮质醇类似物、醋酸可的松或雌激素会增加果蝇对酵母菌攻击的敏感性。为了了解这种类固醇诱导的免疫抑制的机制，我们鉴定了最接近的遗传 GR 同源物：黑腹果蝇雌激素相关受体 (ERR) 基因。我们发现，果蝇 ERR 对于醋酸可的松和雌激素介导的真菌感染敏感性增加是必需的：虽然 ERR 突变型果蝇与野生型果蝇一样对真菌挑战敏感，但 ERR 突变型果蝇的酵母敏感性并没有因此而增加。类固醇。有趣的是，真菌可的松类似物麦角甾醇并没有增加果蝇对酵母菌感染的易感性。类固醇对果蝇对真菌敏感性的免疫抑制作用在昆虫中是进化保守的，因为我们发现雌激素显着增加了致倦库蚊的酵母敏感性，其基因组包含果蝇 ERR 基因的密切直系同源物。这项研究鉴定出黑腹果蝇基因，该基因在结构上类似于脊椎动物的 GR，并且在功能上对于类固醇介导的真菌感染免疫抑制是必需的。