Structural modeling reveals phage proteins that manipulate bacterial immune signaling
Summary
Immune systems in animals, plants, and bacteria often rely on intracellular nucleotide signaling, which viruses can block by sequestering or degrading these signals. We identified structural and biophysical traits shared by diverse viral antidefense proteins and used these traits to develop a computational pipeline that predicts phage proteins whose role is to manipulate bacterial immune signaling. Experimental validation revealed three previously uncharacterized protein families-Sequestin
Content
# Structural modeling reveals phage proteins that manipulate bacterial immune signaling
*Published: 2026 Mar 5*
Immune systems in animals, plants, and bacteria often rely on intracellular
nucleotide signaling, which viruses can block by sequestering or degrading these
signals. We identified structural and biophysical traits shared by diverse viral
antidefense proteins and used these traits to develop a computational pipeline
that predicts phage proteins whose role is to manipulate bacterial immune
signaling. Experimental validation revealed three previously uncharacterized
protein families-Sequestin, Lockin, and Acb5-that inhibit the Thoeris system and
the cyclic oligonucleotide-based antiphage signaling system (CBASS). Sequestin
and Lockin act as nucleotide "sponges," binding 1″-3' glycocyclic adenosine
diphosphate-ribose (3'cADPR) and histidine conjugated to ADPR (His- ADPR),
whereas Acb5 cleaves cyclic guanosine monophosphate-adenosine monosphosphate
(3'3'-cGAMP) and related molecules. Structural and mutational analyses explain
their binding and catalytic mechanisms. Thousands of homologs occur in phage
genomes, highlighting the abundance and diversity of viral strategies to subvert
nucleotide-based immunity.
DOI: 10.1126/science.aea1761