Recurrent acquisition of nuclease-protease pairs in antiviral immunity
- Owen T. Tuck
- Jason J. Hu
- Santiago C. Lopez
- Benjamin A. Adler
- Claire E. O’Brien
- Kendall Hsieh
- Charlotte Meredith
- Kenneth J. Loi
- Peter H. Yoon
- Erin E. Doherty
- Arushi Lahiri
- Jennifer A. Doudna
2025-11-13
Antiviral immune systems diversify by integrating new genes into existing pathways, creating new mechanisms of viral resistance. We identified genes encoding a predicted nuclease paired with a trypsin-like protease repeatedly acquired by multiple, otherwise unrelated antiviral immune systems in bacteria. Cell-based and biochemical assays revealed that the nuclease is a proenzyme that cleaves DNA only after activation by its partner protease. Two distinct immune systems, Hachiman and AVAST (antiviral adenosine triphosphatase/nucleoside triphosphatase of the STAND superfamily, Avs), use the same mechanism of proteolytic activation despite their independent evolutionary origins. Examination of nuclease-protease inheritance patterns identified caspase-nuclease ( canu ) genomic loci that confer antiviral defense in a pathway reminiscent of eukaryotic caspase activation. These results uncover the coordinated activities of pronucleases and their activating proteases within different immune systems and show how coevolution enables defense system innovation.