College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu 210023, China.
Proc Natl Acad Sci U S A. 2023 Aug;120(31):e2304687120. doi: 10.1073/pnas.2304687120. Epub 2023 Jul 24.
Discriminating self from nonself is fundamental to immunity. Yet, it remains largely elusive how the mechanisms of self and nonself discrimination originated. Sensing double-stranded RNA as nonself, the 2',5'-oligoadenylate synthetase (OAS)-ribonuclease L (RNase L) pathway represents a crucial component of innate immunity. Here, we combine phylogenomic and functional analyses to show that the functional OAS-RNase L pathway likely originated through tinkering with preexisting proteins before the rise of jawed vertebrates during or before the Silurian period (444 to 419 Mya). Multiple concerted losses of OAS and RNase L occurred during the evolution of jawed vertebrates, further supporting the ancient coupling between OAS and RNase L. Moreover, both and genes evolved under episodic positive selection across jawed vertebrates, suggesting a long-running evolutionary arms race between the OAS-RNase L pathway and microbes. Our findings illuminate how an innate immune pathway originated via molecular tinkering.
自我与非我之间的区分是免疫的基础。然而，自我和非我区分机制的起源在很大程度上仍然难以捉摸。双链 RNA 被视为非我，2'，5'-寡聚腺苷酸合成酶 (OAS)-核糖核酸酶 L (RNase L) 途径是先天免疫的重要组成部分。在这里，我们结合系统发育和功能分析表明，功能 OAS-RNase L 途径可能起源于有颌脊椎动物出现之前或期间的志留纪时期（4.44 亿至 4.19 亿年前），通过对现有蛋白质进行修补。在有颌脊椎动物的进化过程中，OAS 和 RNase L 发生了多次协同缺失，进一步支持了 OAS 和 RNase L 之间的古老耦合关系。此外， 和 基因在有颌脊椎动物中经历了间歇性正选择进化，这表明 OAS-RNase L 途径和微生物之间存在长期的进化军备竞赛。我们的研究结果阐明了先天免疫途径如何通过分子修补而起源。
