Spotlight Publications

Bacterial 2',3'-cGAMP activates a SAVED effector to form membrane-disrupting filaments and restrict phage replication

Aaron Whiteley — Fri, 27 Mar 2026 15:00:00 +0000

Bacterial 2',3'-cGAMP activates a SAVED effector to form membrane-disrupting filaments and restrict phage replication Aaron Whiteley Fri, 03/27/2026 - 09:00

Uday Tak , Kate Schinkel , Peace Walth , Jian Wei Tay , Erik Hartwick , Aaron Whiteley

Cell Host Microbe (2026). PubMed PMID: 41903528

Abstract

Mammalian cells initiate antiviral signaling when cyclic GMP-AMP synthase (cGAS) detects cytoplasmic DNA and synthesizes 2',3'-cyclic GMP-AMP (2',3'-cGAMP), which activates stimulator of interferon genes (STING). Similarly, bacteria use cyclic oligonucleotide-based antiphage signaling systems (CBASS) to detect phage using ancestral cGAS/DncV-like nucleotidyltransferases (CD-NTases), but they are not known to use 2',3'-cGAMP. Here, we discover a bacterial CD-NTase that produces 2',3'-cGAMP to activate a Saf-2TM-SMODS-associated fused to various effector domains (SAVED) effector (CD-NTase-associated protein 14 [Cap14]), which initiates membrane disruption to restrict phage replication. Cryo-electron microscopy (cryo-EM) reveals that Cap14 binds 2',3'-cGAMP to form a filament, while electrophysiology suggests that cGAMP activates membrane disruption. Swapping the Cap14 transmembrane domain with a nuclease domain yields a functional chimera that exclusively responds to 2',3'-cGAMP. We hypothesize that other predicted transmembrane effectors in CBASS operons disrupt membranes, and we confirm this by showing that bacterial STING homologs with transmembrane domains restrict phage through membrane disruption. These findings expand our understanding of cGAS-STING-like pathways in bacterial immunity.

News and Commentaries

Read Uday's Thread [BlueSky]

Citation

Tak U, Schinkel K, Walth P, Tay JW, Hartwick EW, Whiteley AT. Bacterial 2',3'-cGAMP activates a SAVED effector to form membrane-disrupting filaments and restrict phage replication.Cell Host Microbe. 2026 Mar 27;. doi: 10.1016/j.chom.2026.03.004. [Epub ahead of print] PubMed PMID: 41903528; NIHMSID:NIHMS2161427.

Tak U, Schinkel K, Walth P, Tay JW, Hartwick EW, ➤Whiteley AT | Cell Host Microbe 2026

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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; PubMed Central PMCID: PMC12657218

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]
UCI Scientists Help Uncover a New Bacterial Defense System Against Viruses [UC Irvine]
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 Nov;647(8091):988-996. doi: 10.1038/s41586-025-09557-z. Epub 2025 Oct 1. PMID: 41034579; PMCID: PMC12657218.

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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Functional amyloid proteins confer defence against predatory bacteria

Aaron Whiteley — Wed, 02 Jul 2025 15:00:00 +0000

Functional amyloid proteins confer defence against predatory bacteria Aaron Whiteley Wed, 07/02/2025 - 09:00

Hannah Ledvina , Ryan Sayegh , Ricardo Carale , Burroughs AM , Alexa Macklin , Azadeh AL , Layla Borja , Aravind L , Aaron Whiteley

Nature (2025). PubMed PMID: 40604283; PubMed Central PMCID: PMC12419547

Abstract

Bdellovibrio bacteriovorus is a predatory bacterium that non-selectively preys on Gram-negative bacteria by invading the prey-cell periplasm, leaching host nutrients and ultimately lysing the infected cell to exit and find a new host. The predatory life cycle of B. bacteriovorus is, in many ways, comparable to a bacteriophage. However, unlike phage defence, defence against B. bacteriovorus has not been widely investigated. Here we screened a collection of diverse Escherichia coli strains for resistance to B. bacteriovorus and identified that roughly one-third of strains robustly defended against predation by producing curli fibres. Curli fibres are oligomers of the functional amyloid protein CsgA, which is exceptionally durable3. Using genetics and microscopy, we demonstrate that curli fibres provide a barrier that protects susceptible cells independent of genes required for biofilm formation. This barrier further protected E. coli against attack by the predatory bacterium Myxococcus xanthus and select phages. Bioinformatic analysis of bacterial amyloids showed these systems are diverse and widespread in diderm bacteria (those with both inner and outer membranes). One of these, an evolutionarily distinct amyloid encoded by Pseudomonas aeruginosa, also protected against B. bacteriovorus. This work establishes that functional amyloids defend bacteria against a wide range of threats.

News and Commentaries

When predators meet the matrix: Natural resistance via amyloid fibers [Cell Host & Microbe]
In microbial wars, bacteria suit up with a protein linked to Alzheimer’s [CU Boulder Today]
Read Hannah's Thread [BlueSky]

Citation

Ledvina HE, Sayegh R, Carale RO, Burroughs AM, Macklin AR, Azadeh AL, Borja Najera LD, Aravind L, Whiteley AT. Functional amyloid proteins confer defence against predatory bacteria. Nature. 2025 Aug;644(8075):197-204. doi: 10.1038/s41586-025-09204-7. Epub 2025 Jul 2. PubMed PMID: 40604283; PubMed Central PMCID: PMC12419547.

Ledvina HE, Sayegh R, Carale RO, Burroughs AM, Macklin AR, Azadeh AL, Borja Najera LD, Aravind L, ➤Whiteley AT | Nature 2025

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Bacterial 2',3'-cGAMP activates a SAVED effector to form membrane-disrupting filaments and restrict phage replication

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The Panoptes system uses decoy cyclic nucleotides to defend against phage

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Functional amyloid proteins confer defence against predatory bacteria

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