探討REGE-1如何透過代謝途徑以促進線蟲存活之研究

Abstract

秀麗隱桿線蟲（Caenorhabditis elegans）以其短暫的生命週期和可操控的遺傳特性成為理想的模式生物。由於在秀麗隱桿線蟲中發現的基因和生理機制普遍存在於人類和其他物種中，透過瞭解同源蛋白質對於線蟲生理的影響，我們能夠更深入地了解該蛋白如何調控生物的生理機制，進而將這些瞭解應用於人類或其他物種。在本研究中，我們發現線蟲中的核糖核酸酶REGE-1（與哺乳動物的核糖核酸酶REGNASE-1同源）會影響線蟲在綠膿桿菌（PA14）感染下的存活率。。透過mRNA-Seq分析，我們在rege-1突變蟲中觀察到了兩個關鍵代謝途徑的基因群變化，即胰島素/類胰島素生長因子1（IGF-1）信號（IIS）途徑和TOR激酶信號途徑。抑制這兩條途徑中的任何一條都可以挽救rege-1突變蟲的低存活率。在胰島素/類胰島素生長因子信號（IIS）途徑中，線蟲daf-2基因可轉譯出人類胰島素樣生長因子1受體（IGF1R）的同源蛋白。研究發現，daf-2突變蟲體在正常條件下的壽命比野生型蟲體長。在daf-2突變蟲體中，基因變化可被分為兩類。第一類基因在daf-2基因突變下而表現量增加，而第二類基因在daf-2基因突變下而表現量減少，並且受到DAF-16/FoxO的調控。當我們在rege-1突變蟲中抑制屬於第二類基因之一的過氧化物酸β-氧化酶acox-1.5的表現時，我們觀察到蟲體脂肪含量顯著增加，並改善了rege-1突變蟲在感染過程中的存活率，並從過往的CHIP實驗中發現它受ETS-4調控。總結起來，我們的研究發現rege-1通過調節代謝途徑來影響宿主防禦的機制。

Due to its rapid life cycle and genetic manipulability, Caenorhabditis elegans (C. elegans) is widely used as a model organism for studying conserved pathways in higher organisms. By regulating post-transcriptional events, living organisms can rapidly respond to environmental stimuli. In this study, we showed that REGE-1 ribonuclease, an ortholog of mammalian Regnase-1, is required for lifespan extension under Pseudomonas aeruginosa (PA14). We found that the excess ets-4 mRNA expression, whose mRNA is post-transcriptional regulated by REGE-1 in C. elegans, was associated with higher susceptibility to PA14 infection in worms. Additionally, we discovered global gene changes in two key metabolic pathways, insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway and TOR (target of rapamycin) kinase signaling pathways, through mRNA-Seq analysis in rege-1 mutant worm. Genetic inhibition of either pathway was sufficient to rescue the poor survival of rege-1 mutant worms. The daf-2 gene encodes an ortholog of the human insulin-like growth factor 1 receptor (IGF1R). Two gene clusters have been identified in the insulin/insulin-like growth factor signaling (IIS) pathway. Class I genes are upregulated in daf-2 mutants, while Class II genes are downregulated in daf-2 mutants, and this regulation is dependent on DAF-16/FoxO. In our study, we observed higher expression of class II in rege-1 mutant worms, which may be targeted by ETS-4 and correlated with a higher susceptibility to PA14 infection. Furthermore, we discovered peroxisome acyl-CoA oxidase ACOX-1.5, which belongs to class II and is predicted to be regulated by ETS-4. When we genetically inhibited acox-1.5, we observed a significant rescue in fat content and improved survival of rege-1 mutant worms during infection. In conclusion, our study has revealed how rege-1 affects host defense by regulating metabolic pathways.