A short prokaryotic Argonaute activates membrane effector to confer antiviral defense

Argonaute (Ago) proteins are widespread nucleic-acid-guided enzymes that recognize targets through com-plementary base pairing. Although, in eukaryotes, Agos are involved in RNA silencing, the functions of pro-karyotic 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 Sulfo-lobus islandicus, together with its two genetically associated proteins, Aga1 and Aga2, provide robust anti-viral protection via abortive infection. Aga2 is a toxic transmembrane effector that binds anionic phospho-lipids 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.

Automated summary

This study reveals a short pAgo protein in the archaeon Sulfolobus islandicus, along with its genetically associated proteins Aga1 and Aga2, provide robust anti-viral protection through abortive infection. Aga2 is a toxic transmembrane effector that binds anionic phospholipids, resulting in membrane depolarization and cell killing. Ago and Aga1 form a stable complex with nucleic acid-directed recognition ability and directly interact with Aga2, suggesting an immune sensing mechanism.