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

Dziugas Sabonis, Carmel Avraham, Renee B. Chang, Allen Lu, Ehud Herbst, Arunas Silanskas, Deividas Vilutis, Azita Leavitt, Erez Yirmiya, Hunter C. Toyoda, Audrone Ruksenaite, Mindaugas Zaremba, Ilya Osterman, Gil Amitai, Philip J. Kranzusch (), Rotem Sorek () and Giedre Tamulaitiene ()
Additional contact information
Dziugas Sabonis: Vilnius University
Carmel Avraham: Weizmann Institute of Science
Renee B. Chang: Harvard Medical School
Allen Lu: Harvard Medical School
Ehud Herbst: Weizmann Institute of Science
Arunas Silanskas: Vilnius University
Deividas Vilutis: Vilnius University
Azita Leavitt: Weizmann Institute of Science
Erez Yirmiya: Weizmann Institute of Science
Hunter C. Toyoda: Harvard Medical School
Audrone Ruksenaite: Vilnius University
Mindaugas Zaremba: Vilnius University
Ilya Osterman: Weizmann Institute of Science
Gil Amitai: Weizmann Institute of Science
Philip J. Kranzusch: Harvard Medical School
Rotem Sorek: Weizmann Institute of Science
Giedre Tamulaitiene: Vilnius University

Nature, 2025, vol. 642, issue 8067, 467-473

Abstract: Abstract 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 moieties2–5. 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.

Date: 2025
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DOI: 10.1038/s41586-025-08930-2

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