TIR domains produce histidine-ADPR as an immune signal in bacteria

• 成果类型: Article
• 署名作者: Sabonis, Dziugas; Avraham, Carmel; Chang, Renee B.; Lu, Allen; Herbst, Ehud; Silanskas, Arunas; Vilutis, Deividas; Leavitt, Azita; Yirmiya, Erez; Toyoda, Hunter C.; Ruksenaite, Audrone; Zaremba, Mindaugas; Osterman, Ilya; Amitai, Gil; Kranzusch, Philip J.; Sorek, Rotem; Tamulaitiene, Giedre
• 署名单位: Vilnius University; Weizmann Institute of Science; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3412
• DOI: 10.1038/s41586-025-08930-2
• 发表日期: 2025-06-12
• 关键词: nad(+) cleavage activity; structure refinement; activation; EVOLUTION

摘要

Toll/interleukin-1 receptor (TIR) domains are central components of pattern recognition immune proteins across all domains of life1,2. In bacteria and plants, TIR-domain proteins recognize pathogen invasion and then produce immune signalling molecules exclusively comprising nucleotide moieties2, 3, 4-5. Here we show that the TIR-domain protein of the type II Thoeris defence system in bacteria produces a unique signalling molecule comprising the amino acid histidine conjugated to ADP-ribose (His-ADPR). His-ADPR is generated in response to phage infection and activates the cognate Thoeris effector by binding a Macro domain located at the C terminus of the effector protein. By determining the crystal structure of a ligand-bound Macro domain, we describe the structural basis for His-ADPR and its recognition and show its role by biochemical and mutational analyses. Our analyses furthermore reveal a family of phage proteins that bind and sequester His-ADPR signalling molecules, enabling phages to evade TIR-mediated immunity. These data demonstrate diversity in bacterial TIR signalling and reveal a new class of TIR-derived immune signalling molecules that combine nucleotide and amino acid moieties.