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PreprintCited by 129Immune Response and Inflammationinterferon and immune responsesBacterial Genetics and Biotechnology

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Cyclic nucleotide-induced superhelical structure activates a bacterial TIR immune effector

Open access
Hogrel, Gaëlle, Guild, Abbie, Graham, Shirley, Rickman, Hannah, Grüschow, Sabine, Bertrand, Quentin, Spagnolo, Laura, White, Malcolm F·2022·Nature
DOI 10.1101/2022.05.04.490601

Preprint — published as 10.1038/s41586-022-05070-9 · Paper page

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Abstract

Cyclic nucleotide signalling is a key component of anti-viral defence in all domains of life, from bacteria to humans. Viral detection activates a nucleotide cyclase to generate a second messenger, resulting in activation of effector proteins. This is exemplified by the metazoan cGAS-STING innate immunity pathway 1 , which originated in bacteria 2 . These defence systems require a sensor domain such as STING or SAVED to bind the cyclic nucleotide, coupled with an effector domain that causes cell death when activated by destroying essential biomolecules 3 . One example is the TIR (Toll/interleukin-1 receptor) domain, which degrades the essential cofactor NAD + when activated in response to pathogen invasion in plants and bacteria 2,4,5 or during nerve cell programmed death 6 . Here, we show that a bacterial anti-viral defence system generates a cyclic tri-adenylate (cA 3 ) signal which binds to a TIR-SAVED effector, acting as the “glue” to allow assembly of an extended superhelical solenoid structure. Adjacent TIR subunits interact to organise and complete a composite active site, allowing NAD + degradation. Our study illuminates a striking example of large-scale molecular assembly controlled by cyclic nucleotides and reveals key details of the mechanism of TIR enzyme activation.

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Metadata

Authors
Hogrel, G., Guild, A., Graham, S., Rickman, H., Grüschow, S., Bertrand, Q., Spagnolo, L., & White, M. F.
Affiliations
  • University of St Andrews (GB)
  • MRC Centre for Regenerative Medicine (GB)
  • Centre National de la Recherche Scientifique (FR)
  • University of Glasgow (GB)
Corresponding author
  • Spagnolo, Laura
  • White, Malcolm F
ORCID
Venue
Nature
Publisher
openRxiv
Published
2022-05-04
Volume
608
Issue
7924
Pages
808-812
ISSN
0028-0836 (ISSN-L)
DOI
10.1101/2022.05.04.490601
OpenAlex
W4291020693
Cited by
129
References
1
Citations by year
2026: 23 · 2025: 30 · 2024: 33 · 2023: 32 · 2022: 11
FWCI
10.12
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • DORA PSI (Paul Scherrer Institute) (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • St Andrews Research Repository (St Andrews Research Repository) (submittedVersion, cc-by)
Funders
  • Agence Nationale de la Recherche (UAR 3518 CNRS-CEA-UGA-EMBL, ANR-17-EURE-0003, ANR-17-EURE-, ANR-17, ANR-10, ANR-10-INBS-0005)
  • Centre National de la Recherche Scientifique (ANR‐17‐EURE‐0003, UAR 3518 CNRS-CEA-UGA-EMBL)
  • French Infrastructure for Integrated Structural Biology (ANR-17-EURE-0003, ANR-10-INBS-0005, ANR-10-INBS-000502, ANR-10-INBS)
  • Medical Research Council (MC_PC_17135)
  • Biotechnology and Biological Sciences Research Council (BB/S000313, BB/S000313/1, BB/T004789, BB/T004789/1, MC_PC_17135, UAR 3518 CNRS-CEA-UGA-EMBL, H17007)
  • H2020 European Research Council (101018608)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Keywords
TIR domain, NAD+ degradation, filament assembly, innate immunity, cGAS
MeSH terms
Animals, Antiviral Agents, Bacteria, Bacterial Proteins, NAD, Nucleotides, Cyclic, Second Messenger Systems, Receptors, Interleukin-1, Toll-Like Receptors

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