Pharmacological activation of the Integrated Stress Response triggers a transcriptional program centered on ribosome biogenesis and function in honey bees. Pharmacological activation of the Integrated Stress Response triggers a transcriptional program centered on ribosome biogenesis and function in honey bees

Seeking to further characterize the effect of Halofuginone in honey bees and to better understand cellular stress pathways in this species more generally, we used RNAseq to identify novel changes in gene expression after its ingestion and observed a striking induction of genes involved in ribosome biogenesis, translation, tRNA synthesis, and ribosome-associated quality control (RQC). Feeding bees cycloheximide (CHX) to halt ribosome translocation also induced all tested target genes, suggesting that this gene expression program could be induced by ribosome stalling in addition to tRNA-synthetase inhibition. Only a subset of these ribosome biogenesis genes are upregulated by UPR induction, suggesting that the ISR induces overlapping but distinct responses depending on the mode of activation and cross-talk with other cellular signaling pathways. Overall design: Six samples: 3 from honey bees fed Halofuginone, and 3 from honey bees fed DMSO (control).

为进一步解析常山酮（Halofuginone）在蜜蜂中的生物学效应，并更全面地阐明该物种的细胞应激通路，我们通过RNA测序（RNAseq）鉴定了其经口摄入后基因表达的全新变化，观察到核糖体生物发生、翻译、转运RNA（transfer RNA, tRNA）合成以及核糖体相关质量控制（ribosome-associated quality control, RQC）相关基因的显著诱导表达。我们给蜜蜂喂食环己酰亚胺（cycloheximide, CHX）以阻断核糖体易位，同样诱导了所有检测的靶基因，这提示该基因表达程序不仅可由氨酰-tRNA合成酶抑制触发，还可通过核糖体停滞来诱导。仅部分此类核糖体生物发生基因可经未折叠蛋白反应（unfolded protein response, UPR）诱导上调，这表明整合应激反应（integrated stress response, ISR）的激活模式不同时，其所介导的应答既存在重叠又具有特异性，且会与其他细胞信号通路发生交叉对话。实验总体设计：共设置6个样本，其中3份取自喂食常山酮的蜜蜂，另外3份取自喂食二甲基亚砜（dimethyl sulfoxide, DMSO）的蜜蜂作为对照。