A trapped catalytic product acts as molecular glue for innate immune signalosome assembly

Innate immune systems of living organisms are essential for host defense. Central to these systems is the Toll/interleukin-1 receptor (TIR) domain, an evolutionarily conserved module. From antiphage systems in prokaryotes to innate immune systems in plants, TIR domains have catalytic activity. However, TIR domains within animal innate immune receptors, such as Toll-like receptors (TLRs), have been considered as scaffolds for adaptor recruitment. We report that the TLR4 TIR domain possesses an allosterically activated nicotinamide adenine dinucleotide (NAD + ) hydrolase (NADase) activity that operates in a single-turnover manner. Its product, adenosine diphosphate ribose, is not released but entrapped as a “molecular glue,” stabilizing a composite catalytic pocket with adaptor TIR domain–containing adaptor protein (TIRAP) to nucleate signalosome assembly. This “produce-and-trap” mechanism represents a signaling mode that integrates enzymatic activity with adaptor function to drive downstream signaling.