Argonaute proteins (Agos) represent a diverse family of defence proteins against plasmids and viruses that bind to nucleic acid guides that direct the recognition of nucleic acid targets through complementary base pairing. Agos were first discovered in eukaryotes and shown to be involved in RNA silencing. Prokaryotic Agos (pAgos) have been identified in bacteria and archaea, and their DNA interference activity is an essential part of immunity against invaders. Short pAgos are truncated and catalytically inactive nucleases and, currently, the underlying mechanism of action is not known. In this study, Zeng et al. report that a short pAgo from the archaeon Sulfolobus islandicus and its genetically associated proteins Aga1 and Aga2 confer antiviral defence by abortive infection (Abi).
Abi defence systems include a sensor module and a killer module; the sensor senses viral infection and activates the killer module. As all three proteins, pAgo, Aga1 and Aga2, were essential to confer antiviral immunity in S. islandicus, the authors next determined the role of each of the proteins. The experiments revealed that Aga2 is the toxic effector of the pAgo system. Specifically, Aga2 is a transmembrane protein that forms large oligomers and also binds to the anionic head groups of phospholipids in the membrane, which results in membrane depolarization and thus cell death. Moreover, the authors showed that the Ago–Aga1 complex possesses guide-directed target nucleic acid recognition ability (thus, representing the sensor module), whereby Ago, but not Aga1, exhibits nucleic acid binding activity. However, Ago guide and target binding were increased in the presence of Aga1, which suggests that Aga1 assists in nucleic acid binding. But how do the sensor and killer modules interact to confer antiviral defence? The authors showed that Ago forms a complex with Aga1 in the cytoplasm and that a small fraction of the Ago–Aga1 complex interacts with Aga2 at the membrane to form a ternary complex. Upon viral infection, more Ago–Aga1 complexes are recruited to the membrane, most likely to activate Aga2 cytotoxicity.
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