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Peer-reviewedCC BYNature Communications

Phage-encoded factor stimulates DNA degradation by the Hna anti-phage defense system

  • Matthew M. Hooper1,2,3
  • Benjamin T. Hoover1,3
  • Hongshan Zhang4,1,3
  • Adam S. Franco1,3
  • Ilya J. Finkelstein4,1,3
  • David Ward Taylor5,6,7,8,3
8 affiliations
  1. 1Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA
  2. 2Interdisciplinary Life Sciences Graduate Programs, Austin, TX, USA
  3. 3University of Texas at Austin
  4. 4Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, TX, USA
  5. 5Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, TX, USA. [email protected]
  6. 6Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA. [email protected]
  7. 7Interdisciplinary Life Sciences Graduate Programs, Austin, TX, USA. [email protected]
  8. 8LIVESTRONG Cancer Institutes, Dell Medical School, Austin, TX, USA. [email protected]
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Abstract

Prokaryotic organisms have evolved unique strategies to acquire immunity against the constant threat of bacteriophage (phage) and mobile genetic elements. Hna is a broadly distributed anti-phage immune system that confers resistance against diverse phage by eliciting an abortive infection response. Using a combination of biochemistry, cryo-electron microscopy, and single-molecule fluorescence imaging, we reveal that Hna functions as a 3'-5' single-stranded DNA exonuclease that forms an auto-inhibited dimer under physiological ATP concentrations. Biochemical and mutational analyses demonstrate that Hna catalytic outputs are governed by kinetic partitioning between ATPase and nuclease active sites. Disruption of this balance enhances DNA cleavage and causes cellular toxicity. Furthermore, we show that a phage-encoded single-stranded DNA-binding protein (5 A SSB) destabilizes the autoinhibited Hna dimer and shifts catalytic partitioning toward dysregulated nuclease activation. Conversely, phage escape mutants encode SSB variants that evade Hna surveillance by adopting higher order stoichiometries with enhanced DNA binding affinity. Our work establishes the molecular basis of Hna-mediated anti-phage activity and provides insights into how phage-encoded proteins can directly stimulate a bacterial immune response.

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Cite

BibTeXRIS
BibTeX
@article{hooper2026phageencoded,
  title = {{Phage-encoded factor stimulates DNA degradation by the Hna anti-phage defense system}},
  author = {Matthew M. Hooper and Benjamin T. Hoover and Hongshan Zhang and Adam S. Franco and Ilya J. Finkelstein and David Ward Taylor},
  journal = {Nature Communications},
  year = {2026},
  month = may,
  doi = {10.1038/s41467-026-73157-2},
  url = {https://doi.org/10.1038/s41467-026-73157-2},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Phage-encoded factor stimulates DNA degradation by the Hna anti-phage defense system
AU  - Matthew M. Hooper
AU  - Benjamin T. Hoover
AU  - Hongshan Zhang
AU  - Adam S. Franco
AU  - Ilya J. Finkelstein
AU  - David Ward Taylor
PY  - 2026
DA  - 2026/05/18
JO  - Nature Communications
DO  - 10.1038/s41467-026-73157-2
UR  - https://doi.org/10.1038/s41467-026-73157-2
AB  - Prokaryotic organisms have evolved unique strategies to acquire immunity against the constant threat of bacteriophage (phage) and mobile genetic elements. Hna is a broadly distributed anti-phage immune system that confers resistance against diverse phage by eliciting an abortive infection response. Using a combination of biochemistry, cryo-electron microscopy, and single-molecule fluorescence imaging, we reveal that Hna functions as a 3'-5' single-stranded DNA exonuclease that forms an auto-inhibited dimer under physiological ATP concentrations. Biochemical and mutational analyses demonstrate that Hna catalytic outputs are governed by kinetic partitioning between ATPase and nuclease active sites. Disruption of this balance enhances DNA cleavage and causes cellular toxicity. Furthermore, we show that a phage-encoded single-stranded DNA-binding protein (5 A SSB) destabilizes the autoinhibited Hna dimer and shifts catalytic partitioning toward dysregulated nuclease activation. Conversely, phage escape mutants encode SSB variants that evade Hna surveillance by adopting higher order stoichiometries with enhanced DNA binding affinity. Our work establishes the molecular basis of Hna-mediated anti-phage activity and provides insights into how phage-encoded proteins can directly stimulate a bacterial immune response.
SN  - 2041-1723
ER  -