Phage-associated Cas12p nucleases require binding to bacterial thioredoxin for activation and cleavage of target DNA

Jan 6, 2026Nature microbiology

Phage-related Cas12p enzymes need to attach to bacterial thioredoxin to become active and cut target DNA

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Abstract

A cryo-EM-based structural analysis revealed the Cas12p-TrxA-sgRNA-dsDNA complex at 2.67 Å.

Phage-associated nuclease Cas12p forms complexes with the bacterial protein TrxA to facilitate target DNA degradation.
This interaction indicates that bacteriophages can utilize bacterial factors to enhance their own genome degradation capabilities.
TrxA is shown to directly bind to and activate Cas12p, which is linked to its nuclease activity.
The study highlights the complex interactions between phages and bacteria, particularly in the context of CRISPR immunity.

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The evolutionary competition within phage-host systems led to the emergence of CRISPR-Cas defence mechanisms in bacteria and anti-CRISPR elements in bacteriophages. Although anti-CRISPR elements are well characterized, the role of bacterial factors that influence CRISPR-Cas efficacy has been comparatively overlooked. Type V CRISPR-Cas12 systems display striking functional and mechanistic diversity for nucleic acid targeting. Here we use a bioinformatic approach to identify Cas12p, a phage-associated nuclease that forms complexes with the bacterial thioredoxin protein TrxA to enable target DNA degradation. This represents an unexpected phage-bacteria interaction, in which the bacteriophage co-opts a bacterial factor to augment its own genome degradation machinery, potentially against competing phages. Biochemical characterization, cryo-EM-based structural analysis of the Cas12p-TrxA-sgRNA-dsDNA complex at 2.67 Å and bacterial defence assays reveal that TrxA directly binds and activates Cas12p, enabling its nuclease activity and subsequent CRISPR immunity. These findings expand our understanding of the multilayered intricacies of phage-bacteria molecular interactions.

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Phage-associated Cas12p nucleases require binding to bacterial thioredoxin for activation and cleavage of target DNA

Abstract

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