Target-induced Argonaute-HNH filaments confer bacterial immunity

Argonaute proteins provide innate immunity in all domains of life through guide-dependent recognition of invader nucleic acids. While eukaryotic Argonautes (eAgos) act on RNA during RNA interference, prokaryotic Argonautes (pAgos) mainly recognize DNA targets. Many eAgos and some pAgos are active nucleases that directly cleave their targets. In contrast, short pAgos lack the nuclease activity and are co-encoded with additional effectors. Diverse effector domains in short pAgo systems include NADases and tentative nucleases, but their mechanisms of activation remain largely unknown. Here, we characterize SPARHA systems (short prokaryotic argonautes, HNH-associated) encoding HNH nuclease effectors. We show that short pAgo activates the HNH effector after RNA-guided DNA recognition. Target recognition induces formation of filaments of SPARHA with double active sites formed at the interfaces of repetitive HNH domains, which results in indiscriminate collateral degradation of DNA and protects bacterial population from invaders. The results show that pAgos and associated effectors act as modular two-component systems that translate recognition of specific DNA into immune response through assembly of supramolecular complexes, deleterious for invaders and potentially useful for biotechnology.