Cyclic nucleotide-induced helical structure activates a TIR immune effector

Gaëlle Hogrel, Abbie Guild, Shirley Graham, Hannah Rickman, Sabine Grüschow, Quentin Bertrand, Laura Spagnolo*, Malcolm F. White*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)
11 Downloads (Pure)


Cyclic nucleotide signalling is a key component of antiviral defence in all domains of life. 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 pathway1, which originated in bacteria2. These defence systems require a sensor domain to bind the cyclic nucleotide and are often coupled with an effector domain that, when activated, causes cell death by destroying essential biomolecules3. One example is the Toll/interleukin-1 receptor (TIR) domain, which degrades the essential cofactor NAD+ when activated in response to infection in plants and bacteria2,4,5 or during programmed nerve cell death6. Here we show that a bacterial antiviral defence system generates a cyclic tri-adenylate that binds to a TIR–SAVED effector, acting as the ‘glue’ to allow assembly of an extended superhelical solenoid structure. Adjacent TIR subunits interact to organize and complete a composite active site, allowing NAD+ degradation. Activation requires extended filament formation, both in vitro and in vivo. Our study highlights an example of large-scale molecular assembly controlled by cyclic nucleotides and reveals key details of the mechanism of TIR enzyme activation.
Original languageEnglish
Pages (from-to)808–812
Number of pages5
Issue number7924
Early online date10 Aug 2022
Publication statusPublished - 25 Aug 2022


  • Bacterial immune defense system
  • Cryo-electron microscopy
  • TIR domain


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