Cyclic nucleotide-induced helical structure activates a TIR immune effector

Article

关键词: RAY SOLUTION SCATTERING;    ASSEMBLY FORMATION;    DOMAINS;    MACROMOLECULES;    PATHWAY;    COMPLEX;   

DOI  :  10.1038/s41586-022-05070-9

来源: SCIE

【 摘 要 】

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 pathway(1), which originated in bacteria(2). 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 biomolecules(3). 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 bacteria(2,4,5) or during programmed nerve cell death(6). 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.

【 授权许可】

Free