College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu 210023, China.
Sci Adv. 2024 Aug 9;10(32):eado7464. doi: 10.1126/sciadv.ado7464. Epub 2024 Aug 7.
Self and nonself discrimination is fundamental to immunity. However, it remains largely enigmatic how the mechanisms of distinguishing nonself from self originated. As an intracellular nucleic acid sensor, protein kinase R (PKR) recognizes double-stranded RNA (dsRNA) and represents a crucial component of antiviral innate immunity. Here, we combine phylogenomic and functional analyses to show that PKR proteins probably originated from a preexisting kinase protein through acquiring dsRNA binding domains at least before the last common ancestor of jawed vertebrates during or before the Silurian period. The function of PKR appears to be conserved across jawed vertebrates. Moreover, we repurpose a protein closely related to PKR proteins into a putative dsRNA sensor, recapturing the making of PKR. Our study illustrates how a nucleic acid sensor might have originated via molecular tinkering with preexisting proteins and provides insights into the origins of innate immunity.
自我与非我识别是免疫的基础。然而，区分自我与非我的机制是如何起源的，这在很大程度上仍是个谜。蛋白激酶 R（PKR）作为一种细胞内核酸传感器，识别双链 RNA（dsRNA），是抗病毒先天免疫的重要组成部分。在这里，我们通过系统发育和功能分析表明，PKR 蛋白可能是通过在至少在有颌脊椎动物的最后共同祖先之前的志留纪期间或之前，从现有的激酶蛋白中获得 dsRNA 结合域而产生的。PKR 的功能在有颌脊椎动物中似乎是保守的。此外，我们将一种与 PKR 蛋白密切相关的蛋白质重新用作假定的 dsRNA 传感器，重新捕获 PKR 的产生。我们的研究说明了核酸传感器如何通过对现有蛋白质进行分子修饰而产生，并为先天免疫的起源提供了线索。
