Structure and mechanism of the Zorya anti-phage defence system

• 成果类型: Article
• 署名作者: Hu, Haidai; Popp, Philipp F.; Hughes, Thomas C. D.; Roa-Eguiara, Aritz; Rutbeek, Nicole R.; Martin, Freddie J. O.; Hendriks, Ivo Alexander; Payne, Leighton J.; Yan, Yumeng; Humolli, Dorentina; Klein-Sousa, Victor; Songailiene, Inga; Wang, Yong; Nielsen, Michael Lund; Berry, Richard M.; Harms, Alexander; Erhardt, Marc; Jackson, Simon A.; Taylor, Nicholas M. I.
• 署名单位: University of Copenhagen; Humboldt University of Berlin; University of Otago; University of Copenhagen; Swiss Federal Institutes of Technology Domain; ETH Zurich; Vilnius University; Zhejiang University; University of Oxford
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1725
• DOI: 10.1038/s41586-024-08493-8
• 发表日期: 2025-03-27
• 关键词: escherichia-coli; antiviral defense; bacterial; platform; identification; microscopy; capture

摘要

Zorya is a recently identified and widely distributed bacterial immune system that protects bacteria from viral (phage) infections. Three Zorya subtypes have been identified, each containing predicted membrane-embedded ZorA-ZorB (ZorAB) complexes paired with soluble subunits that differ among Zorya subtypes, notably ZorC and ZorD in type I Zorya systems1,2. Here we investigate the molecular basis of Zorya defence using cryo-electron microscopy, mutagenesis, fluorescence microscopy, proteomics and functional studies. We present cryo-electron microscopy structures of ZorAB and show that it shares stoichiometry and features of other 5:2 inner membrane ion-driven rotary motors. The ZorA5B2 complex contains a dimeric ZorB peptidoglycan-binding domain and a pentameric alpha-helical coiled-coil tail made of ZorA that projects approximately 70 nm into the cytoplasm. We also characterize the structure and function of the soluble Zorya components ZorC and ZorD, finding that they have DNA-binding and nuclease activity, respectively. Comprehensive functional and mutational analyses demonstrate that all Zorya components work in concert to protect bacterial cells against invading phages. We provide evidence that ZorAB operates as a proton-driven motor that becomes activated after sensing of phage invasion. Subsequently, ZorAB transfers the phage invasion signal through the ZorA cytoplasmic tail to recruit and activate the soluble ZorC and ZorD effectors, which facilitate the degradation of the phage DNA. In summary, our study elucidates the foundational mechanisms of Zorya function as an anti-phage defence system.