Cyclic nucleotide-induced helical structure activates a TIR immune effector

Hogrel, G., Guild, A., Graham, S., Rickman, H., Grüschow, S., Bertrand, Q., Spagnolo, L. and White, M. F. (2022) Cyclic nucleotide-induced helical structure activates a TIR immune effector. Nature, 608(7924), pp. 808-812. (doi: 10.1038/s41586-022-05070-9) (PMID:35948638)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Guild, Abbie and Spagnolo, Dr Laura
Authors: Hogrel, G., Guild, A., Graham, S., Rickman, H., Grüschow, S., Bertrand, Q., Spagnolo, L., and White, M. F.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Nature
Publisher:Nature Research
ISSN (Online):1476-4687
Published Online:10 August 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Nature 608(7924): 808-812
Publisher Policy:Reproduced in accordance with the publisher copyright policy
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301445The Scottish Macromolecular Imaging Centre (SMIC)David BhellaMedical Research Council (MRC)MC_PC_17135III - Centre for Virus Research
301474The purchase and maintenance of a cryo-electron microscopeDavid BhellaScottish Funding Council (SFC)H17007III - Centre for Virus Research