Structure and mechanism of the Zorya anti-phage defence system

Haidai Hu (), Philipp F. Popp, Thomas C. D. Hughes, Aritz Roa-Eguiara, Nicole R. Rutbeek, Freddie J. O. Martin, Ivo Alexander Hendriks, Leighton J. Payne, Yumeng Yan, Dorentina Humolli, Victor Klein-Sousa, Inga Songailiene, Yong Wang, Michael Lund Nielsen, Richard M. Berry, Alexander Harms, Marc Erhardt (), Simon A. Jackson () and Nicholas M. I. Taylor ()
Additional contact information
Haidai Hu: University of Copenhagen
Philipp F. Popp: Humboldt-Universität zu Berlin
Thomas C. D. Hughes: University of Otago
Aritz Roa-Eguiara: University of Copenhagen
Nicole R. Rutbeek: University of Copenhagen
Freddie J. O. Martin: University of Copenhagen
Ivo Alexander Hendriks: University of Copenhagen
Leighton J. Payne: University of Otago
Yumeng Yan: University of Copenhagen
Dorentina Humolli: ETH Zurich
Victor Klein-Sousa: University of Copenhagen
Inga Songailiene: University of Copenhagen
Yong Wang: Zhejiang University
Michael Lund Nielsen: University of Copenhagen
Richard M. Berry: University of Oxford
Alexander Harms: ETH Zurich
Marc Erhardt: Humboldt-Universität zu Berlin
Simon A. Jackson: University of Otago
Nicholas M. I. Taylor: University of Copenhagen

Nature, 2025, vol. 639, issue 8056, 1093-1101

Abstract: Abstract 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 α-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.

Date: 2025
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DOI: 10.1038/s41586-024-08493-8

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