Argonaute (Ago) proteins are widespread nucleic-acid-guided enzymes that recognize targets through complementary base pairing. Although, in eukaryotes, Agos are involved in RNA silencing, the functions of prokaryotic Agos (pAgos) remain largely unknown. In particular, a clade of truncated and catalytically inactive pAgos (short pAgos) lacks characterization. Here, we reveal that a short pAgo protein in the archaeon Sulfolobus islandicus, together with its two genetically associated proteins, Aga1 and Aga2, provide robust antiviral protection via abortive infection. Aga2 is a toxic transmembrane effector that binds anionic phospholipids via a basic pocket, resulting in membrane depolarization and cell killing. Ago and Aga1 form a stable complex that exhibits nucleic-acid-directed nucleic-acid-recognition ability and directly interacts with Aga2, pointing to an immune sensing mechanism. Together, our results highlight the cooperation between pAgos and their widespread associated proteins, suggesting an uncharted diversity of pAgo-derived immune systems.

Argonaute (Ago) 蛋白是广泛存在的核酸引导酶，可通过互补碱基配对识别靶标。尽管在真核生物中，Agos 参与 RNA 沉默，但原核生物 Agos (pAgos) 的功能在很大程度上仍然未知。特别是，截断和催化失活的 pAgos（短 pAgos）的进化枝缺乏特征。在这里，我们揭示了古细菌Sulfolobus islandicus中的一种短 pAgo 蛋白。连同其两种基因相关蛋白 Aga1 和 Aga2，通过流产感染提供强大的抗病毒保护。Aga2 是一种有毒的跨膜效应器，通过碱性口袋与阴离子磷脂结合，导致膜去极化和细胞杀伤。Ago 和 Aga1 形成一个稳定的复合物，具有核酸导向的核酸识别能力，并与 Aga2 直接相互作用，指向一种免疫传感机制。总之，我们的结果突出了 pAgo 与其广泛存在的相关蛋白之间的合作，表明 pAgo 衍生的免疫系统存在未知的多样性。