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A viral SAVED protein with ring nuclease activity degrades the CRISPR second messenger cA 4
Open accessPreprint — published as 10.1042/bcj20253271
Abstract
Type III CRISPR systems typically generate cyclic oligoadenylate (cOA) second messengers such as cyclic tetra-adenylate (cA 4 ) on detection of foreign RNA, activating ancillary effector proteins which elicit a diverse range of immune responses. The CalpLTS system elicits a transcriptional response to infection when CalpL binds cA 4 in its SAVED (SMODS associated and fused to various effectors domain) sensor domain, resulting in filament formation and activation of the Lon protease domain, which cleaves the anti-Sigma factor CalpT, releasing the CalpS Sigma factor for transcriptional remodelling. Here, we show that thermophilic viruses have appropriated the SAVED domain of CalpL as an anti-CRISPR, AcrIII-2, which they use to degrade cA 4 . AcrIII-2 dimers sandwich cA 4 , degrading it in a shared active site to short linear products, using a mechanism highly reminiscent of CalpL. This results in inhibition of a range of cA 4 activated effectors in vitro . This is the first example of a virally-encoded SAVED domain with ring nuclease activity, highlighting the complex interplay between viruses and cellular defences.
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Metadata
- Authors
- Orzechowski, M., Hoikkala, V., Chi, H., McMahon, S., Gloster, T., & White, M. F.
- Affiliations
- University of St Andrews (GB)
- Corresponding author
- White, Malcolm F
- Venue
- Biochemical Journal
- Publisher
- openRxiv
- Published
- 2025-07-01
- Volume
- 482
- Issue
- 22
- Pages
- 1707-1719
- ISSN
- 0264-6021 (ISSN-L)
- PMC
- PMC12751052
- OpenAlex
- W4415923994
- Cited by
- 1
- References
- 1
- Citations by year
- 2026: 1
- FWCI
- 0.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biochemical Journal (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- St Andrews Research Repository (St Andrews Research Repository) (acceptedVersion, cc-by)
- Funders
- Rheinische Friedrich-Wilhelms-Universität Bonn
- H2020 European Research Council (101018608)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Immunology and Microbiology › Virology › Bacteriophages and microbial interactions
- Keywords
- type III CRISPR-Cas, CALP
- MeSH terms
- Adenine Nucleotides, Oligoribonucleotides, Viral Proteins, Second Messenger Systems, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Cas Systems
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