Cyclic nucleotide-induced superhelical structure activates a bacterial TIR immune effector

ABSTRACT Cyclic nucleotide signalling is a key component of anti-viral defence in all domains of life, from bacteria to humans. 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 pathway 1 , which originated in bacteria 2 . These defence systems require a sensor domain such as STING or SAVED to bind the cyclic nucleotide, coupled with an effector domain that causes cell death when activated by destroying essential biomolecules 3 . One example is the TIR (Toll/interleukin-1 receptor) domain, which degrades the essential cofactor NAD + when activated in response to pathogen invasion in plants and bacteria 2,4,5 or during nerve cell programmed death 6 . Here, we show that a bacterial anti-viral defence system generates a cyclic tri-adenylate (cA 3 ) signal which binds to a TIR-SAVED effector, acting as the “glue” to allow assembly of an extended superhelical solenoid structure. Adjacent TIR subunits interact to organise and complete a composite active site, allowing NAD + degradation. Our study illuminates a striking example of large-scale molecular assembly controlled by cyclic nucleotides and reveals key details of the mechanism of TIR enzyme activation.