Structure-guided insights into TIR-mediated bacterial and eukaryotic immunity

Within the course of evolution, TIR (Toll/interleukin-1 receptor) domains acquired a myriad of functional specificities. This has significantly added to their well-established roles in innate immune signaling. These additional functions include nicotinamide adenine dinucleotide (NAD)(P) hydrolase, RNA/DNA nuclease (in plants), CN (cyclic nucleotide) cyclase, and base exchanger activities. Owing to these diverse functions, TIR domains can either generate CN second messengers or act as effectors, many of which can accomplish depletion of the essential metabolite NAD⁺, leading to cell death prior to pathogen-induced cell lysis. Despite their functional diversity, activated TIR domains have retained their ability to form multimers that adopt varying topologies, thereby creating composite NADase active sites between adjacent TIR monomers. This structure-based review on the functional diversity of TIR domains focuses primarily across bacterial antiphage defense systems while also addressing their eukaryotic counterparts, throughout highlighting multimerization, including filament formation, as the conserved topological characteristic.