A DNA-gated molecular guard controls bacterial Hailong anti-phage defence

Joel M. J. Tan, Sarah Melamed, Joshua C. Cofsky, Deepsing Syangtan, Samuel J. Hobbs, Josefina Mármol, Marco Jost, Andrew C. Kruse, Rotem Sorek and Philip J. Kranzusch ()
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Joel M. J. Tan: Harvard Medical School
Sarah Melamed: Weizmann Institute of Science
Joshua C. Cofsky: Harvard Medical School
Deepsing Syangtan: Harvard Medical School
Samuel J. Hobbs: Harvard Medical School
Josefina Mármol: Harvard Medical School
Marco Jost: Harvard Medical School
Andrew C. Kruse: Harvard Medical School
Rotem Sorek: Weizmann Institute of Science
Philip J. Kranzusch: Harvard Medical School

Nature, 2025, vol. 643, issue 8072, 794-800

Abstract: Abstract Animal and bacterial cells use nucleotidyltransferase (NTase) enzymes to respond to viral infection and control major forms of immune signalling including cGAS-STING innate immunity and CBASS anti-phage defence1–4. Here we discover a family of bacterial defence systems, which we name Hailong, that use NTase enzymes to constitutively synthesize DNA signals and guard against phage infection. Hailong protein B (HalB) is an NTase that converts deoxy-ATP into single-stranded DNA oligomers. A series of X-ray crystal structures define a stepwise mechanism of HalB DNA synthesis initiated by a C-terminal tyrosine residue that enables de novo enzymatic priming. We show that HalB DNA signals bind to and repress activation of a partnering Hailong protein A (HalA) effector complex. A 2.0-Å cryo-electron microscopy structure of the HalA–DNA complex reveals a membrane protein with a conserved ion channel domain and a unique crown domain that binds the DNA signal and gates activation. Analysing Hailong defence in vivo, we demonstrate that viral DNA exonucleases required for phage replication trigger release of the primed HalA complex and induce protective host cell growth arrest. Our results explain how inhibitory nucleotide immune signals can serve as molecular guards against phage infection and expand the mechanisms NTase enzymes use to control antiviral immunity.

Date: 2025
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DOI: 10.1038/s41586-025-09058-z

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