Cyclic nucleotide-induced helical structure activates a TIR immune effector

Gaëlle Hogrel, Abbie Guild, Shirley Graham, Hannah Rickman, Sabine Grüschow, Quentin Bertrand, Laura Spagnolo () and Malcolm F. White ()
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Gaëlle Hogrel: School of Biology, University of St Andrews
Abbie Guild: Institute of Molecular, Cell and Systems Biology, University of Glasgow
Shirley Graham: School of Biology, University of St Andrews
Hannah Rickman: School of Biology, University of St Andrews
Sabine Grüschow: School of Biology, University of St Andrews
Quentin Bertrand: Université Grenoble Alpes, CNRS, CEA, IBS
Laura Spagnolo: Institute of Molecular, Cell and Systems Biology, University of Glasgow
Malcolm F. White: School of Biology, University of St Andrews

Nature, 2022, vol. 608, issue 7924, 808-812

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-05070-9

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