Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
School of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
PLoS Genet. 2023 Aug 9;19(8):e1010869. doi: 10.1371/journal.pgen.1010869. eCollection 2023 Aug.
Metabolic pathways are known to sense the environmental stimuli and result in physiological adjustments. The responding processes need to be tightly controlled. Here, we show that upon encountering P. aeruginosa, C. elegans upregulate the transcription factor ets-4, but this upregulation is attenuated by the ribonuclease, rege-1. As such, mutants with defective REGE-1 ribonuclease activity undergo ets-4-dependent early death upon challenge with P. aeruginosa. Furthermore, mRNA-seq analysis revealed associated global changes in two key metabolic pathways, the IIS (insulin/IGF signaling) and TOR (target of rapamycin) kinase signaling pathways. In particular, failure to degrade ets-4 mRNA in activity-defective rege-1 mutants resulted in upregulation of class II longevity genes, which are suppressed during longevity, and activation of TORC1 kinase signaling pathway. Genetic inhibition of either pathway way was sufficient to abolish the poor survival phenotype in rege-1 worms. Further analysis of ETS-4 ChIP data from ENCODE and characterization of one upregulated class II gene, ins-7, support that the Class II genes are activated by ETS-4. Interestingly, deleting an upregulated Class II gene, acox-1.5, a peroxisome β-oxidation enzyme, largely rescues the fat lost phenotype and survival difference between rege-1 mutants and wild-types. Thus, rege-1 appears to be crucial for animal survival due to its tight regulation of physiological responses to environmental stimuli. This function is reminiscent of its mammalian ortholog, Regnase-1, which modulates the intestinal mTORC1 signaling pathway.
代谢途径已知能够感知环境刺激，并导致生理调节。这些反应过程需要被严格控制。在这里，我们发现，当遇到绿脓杆菌时，秀丽隐杆线虫会上调转录因子 ets-4，但这种上调被核糖核酸酶 rege-1 减弱。因此，在遇到绿脓杆菌时，rege-1 核糖核酸酶活性缺陷的突变体会经历依赖于 ets-4 的早期死亡。此外，mRNA-seq 分析显示，两个关键代谢途径（胰岛素/IGF 信号通路和 TOR（雷帕霉素靶蛋白）激酶信号通路）发生了相关的全局变化。特别是，在活性缺陷的 rege-1 突变体中，ets-4 mRNA 无法降解，导致 II 类长寿基因上调，这些基因在长寿期间受到抑制，同时激活了 TORC1 激酶信号通路。这两种途径的遗传抑制足以消除 rege-1 蠕虫中较差的生存表型。对 ENCODE 中的 ETS-4 ChIP 数据进行进一步分析，并对一个上调的 II 类基因 ins-7 进行特征分析，支持 ETS-4 激活了 II 类基因。有趣的是，删除一个上调的 II 类基因 acox-1.5，一种过氧化物酶体β-氧化酶，在很大程度上挽救了 rege-1 突变体和野生型之间丢失的脂肪表型和生存差异。因此，rege-1 似乎由于其对环境刺激的生理反应的严格调节，对于动物的生存至关重要。这一功能让人联想到其哺乳动物同源物 Regnase-1，它调节肠道 mTORC1 信号通路。
