Li Yao, Toyoda Hunter C, Fernandez Samantha G, Tiwari Bianca, McNairy Collin, Woznica Arielle, Kranzusch Philip J
Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
bioRxiv. 2025 Sep 4:2025.09.04.674280. doi: 10.1101/2025.09.04.674280.
Animal innate immunity evolved from ancient pathways in bacterial anti-phage defense. How bacterial immune components were first acquired and adapted within eukaryotic cells remains poorly understood. Here we identify a complete cGLR-STING signaling axis in choanoflagellates, the closest living relatives of animals, that exhibits a mosaic of features from both bacterial and animal immunity. Comparative genomics reveals choanoflagellate and genes organized in operon-like arrangements reminiscent of bacterial defense loci. Reconstitution of choanoflagellate cGLR-STING signaling demonstrates that activation occurs through the conserved nucleotide immune signal 2'3'-cGAMP. Structural analysis of a choanoflagellate STING-2'3'-cGAMP complex explains how retention of bacterial-like features in early eukaryotic proteins shapes ligand specificity and receptor activation. We analyze and evolution in unicellular eukaryotes and identify further STING homologs in choanoflagellates and fungi that support additional independent acquisition events. Our results reveal molecular fossils that bridge bacterial and animal immunity and illuminate early eukaryotic immune system evolution.
动物的先天免疫起源于细菌抗噬菌体防御的古老途径。细菌免疫成分最初是如何在真核细胞中获得并适应的，目前仍知之甚少。在这里，我们在领鞭毛虫（动物现存的亲缘关系最近的生物）中鉴定出了一个完整的cGLR-STING信号轴，它展现出细菌免疫和动物免疫的混合特征。比较基因组学研究表明，领鞭毛虫的 和 基因以类似操纵子的形式排列，这让人联想到细菌的防御基因座。对领鞭毛虫cGLR-STING信号的重建表明，其激活是通过保守的核苷酸免疫信号2'3'-cGAMP实现的。对领鞭毛虫STING-2'3'-cGAMP复合物的结构分析解释了早期真核生物蛋白质中类似细菌的特征是如何塑造配体特异性和受体激活的。我们分析了单细胞真核生物中的 和 进化，并在领鞭毛虫和真菌中鉴定出了更多的STING同源物，这些同源物支持了更多独立的获得事件。我们的研究结果揭示了连接细菌免疫和动物免疫的分子化石，并阐明了早期真核生物免疫系统的进化。
