Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
RNA. 2020 Feb;26(2):126-136. doi: 10.1261/rna.073825.119. Epub 2019 Nov 18.
At the heart of an innate immune response lies a tightly regulated gene expression program. This precise regulation is crucial because small changes can shift the balance from protective to destructive immunity. Here we identify a frequently used alternative splice site in the gene oligoadenylate synthetase 1g (), a key component of the 2-5A antiviral system. Usage of this splice site leads to the generation of a transcript subject to decay, and removal of the site leads to increased expression of and an improved antiviral response. However, removal of the splice site also leads to an increase in apoptotic cell death, suggesting this splicing event exists as a compromise between the pathogen protective benefits and collateral damage associated with OAS1g activity. Across the innate immune response, we show that a multitude of alternative splicing events predicted to lead to decay exist, and thus have the potential to play a significant role in the regulation of gene expression in innate immunity.
在先天免疫反应的核心，存在一个受到严格调控的基因表达程序。这种精确的调控至关重要，因为微小的变化可能会使保护性免疫和破坏性免疫之间的平衡发生倾斜。在这里，我们在基因寡腺苷酸合成酶 1g (OAS1g)中发现了一个经常使用的可变剪接位点，该基因是 2-5A 抗病毒系统的关键组成部分。该剪接位点的使用会导致一个易降解的转录本的产生，而去除该剪接位点会导致 OAS1g 的表达增加，并增强抗病毒反应。然而，去除剪接位点也会导致凋亡细胞死亡增加，这表明这种剪接事件是病原体保护益处与 OAS1g 活性相关的附带损伤之间的一种妥协。在整个先天免疫反应中，我们表明，存在大量可能导致降解的可变剪接事件，因此它们有可能在先天免疫中基因表达的调控中发挥重要作用。
