Modularity of Zorya defense systems during phage inhibition

Giuseppina Mariano (), Justin C. Deme (), Jennifer J. Readshaw, Matthew J. Grobbelaar, Mackenzie Keenan, Yasmin El-Masri, Lindsay Bamford, Suraj Songra, Tim R. Blower, Tracy Palmer and Susan M. Lea ()
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Giuseppina Mariano: University of Glasgow
Justin C. Deme: NIH
Jennifer J. Readshaw: Durham University
Matthew J. Grobbelaar: Durham University
Mackenzie Keenan: University of Glasgow
Yasmin El-Masri: University of Glasgow
Lindsay Bamford: University of Glasgow
Suraj Songra: University of Glasgow
Tim R. Blower: Durham University
Tracy Palmer: Newcastle University
Susan M. Lea: NIH

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Bacteria have evolved an extraordinary diversity of defense systems against bacteriophage (phage) predation. However, the molecular mechanisms underlying these anti-phage systems often remain elusive. Here, we provide mechanistic and structural insights into Zorya phage defense systems. Using cryo-EM structural analyses, we show that the Zorya type I and II core components, ZorA and ZorB, assemble in a 5:2 complex that is similar to inner-membrane ion-driven, rotary motors that power flagellar rotation, type 9 secretion, gliding and the Ton nutrient uptake systems. The ZorAB complex has an elongated cytoplasmic tail assembled by bundling the C-termini of the five ZorA subunits. Mutagenesis demonstrates that peptidoglycan binding by the periplasmic domains of ZorB, the structured cytoplasmic tail of ZorA, and ion flow through the motor is important for function in both type I and II systems. Furthermore, we identify ZorE as the effector module of the Zorya II system, possessing nickase activity. Our work reveals the molecular basis of the activity of Zorya systems and highlights the ZorE nickase as crucial for population-wide immunity in the type II system.

Date: 2025
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DOI: 10.1038/s41467-025-57397-2

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