The Panoptes system uses decoy cyclic nucleotides to defend against phage

Aaron Whiteley — Wed, 01 Oct 2025 15:00:00 +0000

The Panoptes system uses decoy cyclic nucleotides to defend against phage Aaron Whiteley Wed, 10/01/2025 - 09:00

Ashley Sullivan , Ali Nabhani , Daniel S Izrailevsky , Kate Schinkel , Charlotte Hoffman , Laurel Robbins , Toni Nagy , Melissa Duncan , Hannah Ledvina , Annette Erbse , Emily Kibby , Uday Tak , David Dinh , Eirene Ednacot , Christy Nguyen , A Maxwell Burroughs , L Aravind , Aaron Whiteley , Benjamin Morehouse

Nature (2025). PubMed PMID: 41034579

Abstract

Bacteria combat phage infection using antiphage systems and many systems generate nucleotide-derived second messengers upon infection that activate effector proteins to mediate immunity. Phages respond with counter-defences that deplete these second messengers, leading to an escalating arms race with the host. Here we outline an antiphage system we call Panoptes that indirectly detects phage infection when phage proteins antagonize the nucleotide-derived second-messenger pool. Panoptes is a two-gene operon, optSE, wherein OptS is predicted to synthesize a nucleotide-derived second messenger and OptE is predicted to bind that signal and drive effector-mediated defence. Crystal structures show that OptS is a minimal CRISPR polymerase (mCpol) domain, a version of the polymerase domain found in type III CRISPR systems (Cas10). OptS orthologues from two distinct Panoptes systems generated cyclic dinucleotide products, including 2',3'-cyclic diadenosine monophosphate (2',3'-c-di-AMP), which we showed were able to bind the soluble domain of the OptE transmembrane effector. Panoptes potently restricted phage replication, but phages that had loss-of-function mutations in anti-cyclic oligonucleotide-based antiphage signalling system (CBASS) protein 2 (Acb2) escaped defence. These findings were unexpected because Acb2 is a nucleotide 'sponge' that antagonizes second-messenger signalling. Our data support the idea that cyclic nucleotide sequestration by Acb2 releases OptE toxicity, thereby initiating inner membrane disruption, leading to phage defence. These data demonstrate a sophisticated immune strategy that bacteria use to guard their second-messenger pool and turn immune evasion against the virus.

News and Commentaries

Bacteria use a decoy defence molecule to set a trap for viruses [Nature]
Read Ashley's Thread [BlueSky]

Citation

Sullivan AE, Nabhani A, Izrailevsky DS, Schinkel K, Hoffman CRK, Robbins LK, Nagy TA, Duncan ML, Ledvina HE, Erbse AH, Kibby EM, Tak U, Dinh DM, Ednacot EMQ, Nguyen CM, Burroughs AM, Aravind L, Whiteley AT, Morehouse BR. The Panoptes system uses decoy cyclic nucleotides to defend against phage. Nature. 2025 Oct 1. doi: 10.1038/s41586-025-09557-z. Epub ahead of print. PMID: 41034579.

Illustration depicting a bacterium under assault by phage. The bacterium “sees” phage immune evasion proteins and protects itself using a newly described antiphage system called Panoptes, named for the many-eyed mythical giant Argus Panoptes. Credit: Clair Huffine Insight Illustrations LLC

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The Panoptes system uses decoy cyclic nucleotides to defend against phage

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