Journal Article

PUBDB-2025-02291

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png TIR domains produce histidine-ADPR as an immune signal in bacteria

Sabonis, D. ; Avraham, C. ; Chang, R. B. ; Lu, A. ; Herbst, E. ; Silanskas, A. ; Vilutis, D. ; Leavitt, A. ; Yirmiya, E. ; Toyoda, H. C. ; Ruksenaite, A. ; Zaremba, M. ; Osterman, I. ; Amitai, G. ; Kranzusch, P. J. (Corresponding author) ; Sorek, R. (Corresponding author) ; Tamulaitiene, G. (Corresponding author)

2025
Nature Publ. Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/s41586-025-08930-2

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 moieties2,3,4,5. 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.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)

Appears in the scientific report 2025

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