Science (New York, N.Y.) ·12 Nov 2026 ·Added 13 Nov 2026

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

Qi Liu, Zhongjian Bai, Tianyi Liu, Fangshuai Jia, Yi Ji, Canxi Chen, Yao Gong, Liuyuan Duan, Jiahui Zhou, Qian Guo, Ling Zhu, Huarui Kang, Haiyong Wang, Zhewen Shen, Xiaoxiang Huang, Jiayi Shen, Wenguang Shao, Junbiao Chang, Jijie Chai, Yixiao Zhang, Zhifu Han, Chenlu Zhang, Zehan Hu

DOI ↗

Abstract

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.