Cyclic nucleotide-induced helical structure activates a TIR immune effector
MetadataShow full item record
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.
Hogrel , G , Guild , A , Graham , S , Rickman , H , Grüschow , S , Bertrand , Q , Spagnolo , L & White , M F 2022 , ' Cyclic nucleotide-induced helical structure activates a TIR immune effector ' , Nature , vol. 608 , no. 7924 , pp. 808–812 . https://doi.org/10.1038/s41586-022-05070-9
Copyright © 2022 the Author(s). This work has been made available online in accordance with publisher policies or with permission. Permission for further reuse of this content should be sought from the publisher or the rights holder. This is the author created accepted manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1038/s41586-022-05070-9.
DescriptionFunding: This work was financed by the Biotechnology and Biological Sciences Research Council (references BB/S000313 and BB/T004789) and a European Research Council Advanced Grant (grant number 101018608) to M.F.W. We acknowledge the Scottish Centre for Macromolecular Imaging, M. Clarke and J. Streetley for assistance with cryo-EM experiments and access to instrumentation, financed by the Medical Research Council (MC_PC_17135) and the Scottish Funding Council (H17007).
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.