In many bacteria, MisB pairs not with MisA but with MisC, a protein with three transmembrane helices.
Together, they form type II Metis — a defense system also activated by m⁶dAMP.
AF3 predictions suggest that MisC could assemble into an octameric pore across the membrane during activation.

Metis doesn’t recognize a specific phage protein — it recognizes a consequence of infection: genome degradation.
Phages can escape Metis by avoiding host DNA degradation (for example, through mutation of the DenA endonuclease), but that escape comes at a cost —they lose access to host nucleotides.

The second gene, MisB, is an m⁶dAMP phosphatase.
Low levels of m⁶dAMP can appear even without phage infection, during normal DNA repair. MisB “cleans” these traces to prevent premature activation and self-toxicity.

We also found that MisA cuts NAD⁺ in a unique way, producing NMN and AMP — unlike any previously known NAD⁺-depleting defense enzymes.
This might prevent phages from rebuilding NAD⁺ through their usual repair pathways (for example, NARP1 - www.nature.com/articles/s41...).

In this work, we identified a two-gene anti-phage defense system, which we named Metis. Upon accumulation of m⁶dAMP, MisA is activated and rapidly depletes NAD⁺, shutting down the cell and preventing phage replication.

We found that bacteria can detect the degradation of their own genome — a hallmark of phage infection.
They do it by sensing the accumulation of a modified nucleotide, N⁶-methyl-deoxyadenosine monophosphate (m⁶dAMP) — a signature molecule that appears when bacterial DNA is broken down.

Bacteria can sense when a virus starts shredding their genome — by detecting methylated mononucleotides.
Here’s the story of how we discovered the Metis defense system 👇
www.biorxiv.org/content/10.1...

Our paper is finally published in Science! 🎉The HPLC, NMR, MS, purification, and characterization of the new molecule felt like a real detective story. I was especially thrilled to use and reference my grandfather, Lev Osterman's, 1966 paper—he was the main reason I became a scientist.

You are right and sorry for this mistake, in the paper it is correct

Thank you and sorry for this mistake, you are absolutely right - in the paper it is correct

Finally moved to #Bluesky
and happy to share our recent work about a new phage anti-defense system, based on NAD reconstitution by new enzymatic reactions.
www.nature.com/articles/s41...