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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

Five years ago, NAD⁺ depletion wasn’t recognized as a bacterial immune strategy. Now we know many systems do this: TIRs, SIRim, SEFIR, aRES, and the MisA effector of Metis www.biorxiv.org/content/10.1.... It’s amazing to watch this field grow.

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

aRES is an abundant defense strategy, found in 4% of bacteria. Its discovery further increases the fraction of bacteria that degrade NAD⁺ for phage defense. This abundance results in the evolution of additional anti-defense genes, including a small phage protein that directly binds and inhibits aRES

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

This extended pathway — NARP1-AP — efficiently protects phages from aRES. All three enzymes are required, and together they also protect against classic NAD-depleting systems like Nezha.

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

Digging deeper into NARP1 operons, we discovered an associated phosphatase gene. This enzyme removes the phosphate from ADPR-1P, converting it back to ADPR — the canonical NARP1 substrate.

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

This subtle chemical modification explains why NARP1 fails: its enzyme cannot use ADPR-1P as a substrate. NARP2 does not rely on ADPR; it uses the host metabolite PRPP, making it largely independent of the exact chemistry of NAD⁺ cleavage — and therefore effective against aRES.

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

Why? NARP1 requires ADPR as a product of NAD⁺ cleavage. But aRES doesn’t just break the bond between nicotinamide and ADPR — it adds a phosphate, generating ADPR-1″-phosphate (ADPR-1P).

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

Recently, we discovered phage anti-defense strategies based on NAD⁺ reconstitution from cleavage products: NARP1 and NARP2 www.nature.com/articles/s41.... Surprisingly, only NARP2 — but not NARP1 — can overcome aRES.

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

RES-domain proteins were previously known from toxin–antitoxin systems and bacterial persistence. We now show that a large standalone RES-domain gene protects bacteria from many phages via NAD⁺-depletion. We named this defense system aRES, after one of the Olympian gods ⚡

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

This extended pathway — NARP1-AP — efficiently protects phages from aRES. All three enzymes are required, and together they also protect against classic NAD-depleting systems like Nezha.

100

Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

Digging deeper into NARP1 operons, we discovered an associated phosphatase gene. This enzyme removes the phosphate from ADPR-1P, converting it back to ADPR — the canonical NARP1 substrate.

100

Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

This subtle chemical modification explains why NARP1 fails: its enzyme cannot use ADPR-1P as a substrate. NARP2 does not rely on ADPR, it uses the host metabolite PRPP, making it largely independent of the exact chemistry of NAD⁺ cleavage — and therefore effective against aRES.

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

Why? NARP1 requires ADPR as a product of NAD⁺ cleavage. But aRES doesn’t just break the bond between nicotinamide and ADPR — it adds a phosphate, generating ADPR-1″-phosphate (ADPR-1P).

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

Five years ago, NAD⁺ depletion wasn’t known as a bacterial immune strategy. Now we know many proteins do this: TIRs, SIRim, SEFIR, aRES, and the MisA effector of Metis www.biorxiv.org/content/10.1... . It’s amazing to watch this field grow!

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

aRES is an abundant defense strategy, found in ~4% of bacteria. Its discovery further increases the fraction of bacteria that degrade NAD⁺ to resist phage infection. This abundance results in the evolution of anti-defense genes, including a small phage protein that directly binds and inhibits aRES.

100

Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

This extended pathway — NARP1-AP — efficiently protects phages from aRES. All three enzymes are required, and together they also protect against classic NAD-depleting systems like Nezha

100

Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

Digging deeper into NARP1 operons, we discovered an associated phosphatase gene. This enzyme removes the phosphate from ADPR-1P, converting it back to ADPR — the canonical NARP1 substrate.

100

Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

Why? NARP1 requires ADPR as a product of NAD⁺ cleavage. But aRES doesn’t just break the bond between nicotinamide and ADPR — it adds a phosphate, generating ADPR-1″-phosphate (ADPR-1P).

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

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Osterman Ilya @ostermanilya.bsky.social · 29/01/2026

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Osterman Ilya @ostermanilya.bsky.social · 06/11/2025

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.

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Osterman Ilya @ostermanilya.bsky.social · 06/11/2025

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.

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Osterman Ilya @ostermanilya.bsky.social · 06/11/2025

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.

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Osterman Ilya @ostermanilya.bsky.social · 06/11/2025

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...).

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Osterman Ilya @ostermanilya.bsky.social · 06/11/2025

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.

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Osterman Ilya @ostermanilya.bsky.social · 06/11/2025

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.

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Osterman Ilya @ostermanilya.bsky.social · 06/11/2025

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...

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Osterman Ilya @ostermanilya.bsky.social · 31/01/2025

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.

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Osterman Ilya @ostermanilya.bsky.social · 23/11/2024

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

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Osterman Ilya @ostermanilya.bsky.social · 23/11/2024

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

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Osterman Ilya @ostermanilya.bsky.social · 21/11/2024

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...

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