A short prokaryotic Argonaute activates membrane effector to confer antiviral defense

• Published in: Cell host & microbe 2022-07, Vol.30 (7), p.930-943.e6
• Main Authors: Zeng, Zhifeng, Chen, Yu, Pinilla-Redondo, Rafael, Shah, Shiraz A., Zhao, Fen, Wang, Chen, Hu, Zeyu, Wu, Chang, Zhang, Changyi, Whitaker, Rachel J., She, Qunxin, Han, Wenyuan
• Format: Article
• Language: English
• Subjects: abortive infection; archaea; membrane depolarization; membrane-associated toxic effector; microbial antiviral defense system; nucleic-acid recognition; phospholipids-interacting protein; prokaryotic Argonaute
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2022.04.015

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. [Display omitted] •Sulfolobusislandicus Ago system provides antiviral defense by abortive infection•Ago-Aga1 complex has nucleic-acid-recognition ability•Aga2 is a toxic membrane protein and binds anionic phospholipids•Ago-Aga1 interacts with Aga2 and activates it to trigger membrane depolarization Zeng et al. find that a short prokaryotic Argonaute (Ago) and its two associated proteins (Aga1 and Aga2) mediate cell death upon viral infection. The process involves Ago and Aga1 for invading nucleic-acid recognition and Aga2, a toxic membrane protein that binds anionic phospholipids and triggers membrane depolarization.