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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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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Guild, Abbie and Spagnolo, Professor 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: | 0028-0836 |
| 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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