Scientists at Gladstone Institutes discovered a bacterial immune system called type VI retrons that operates in reverse compared to all previously known retron defenses. The findings appear in Molecular Cell.
Most retrons keep a toxic protein suppressed with single-stranded DNA. When a virus infects, the DNA's protective effect is disrupted, allowing the toxin to kill the cell and stop viral spread. Type VI retrons work opposite. They produce almost no DNA or toxin in healthy cells. When a phage infects, DNA production spikes sharply. The accumulating DNA interacts with an RNA molecule blocking toxin production, removing that block and allowing rapid toxin creation. The DNA acts as an activation switch rather than a restraint.
Researchers initially suspected the systems were broken because they could not detect the single-stranded DNA normally present in retrons. "The way we typically detect retrons inside uninfected cells is by looking for this single-stranded DNA," says Karen Zhang, a PhD student and lead author. "But type VI retrons caught our attention because they didn't appear to have this signature. It was very odd, and we wondered if they might be broken."
Seth Shipman, senior author and Gladstone Investigator, notes the complexity. "This is, by far, the strangest of the retron systems that we or anyone else has come across," he says. "These retrons operate with Rube Goldberg-level complexity, using molecular mechanisms that we would never have thought to invent, but that we'll use in future technologies."
Standard detection methods repeatedly failed, forcing the team to develop new approaches. A technique called Spacer-seq, which uses CRISPR-Cas machinery to record molecular activity inside cells, finally revealed trace amounts of DNA that earlier experiments had missed.
The discovery could inform development of synthetic molecular sensors and switches that regulate gene activity, with potential medical applications for treating disease and studying how certain diseases operate.