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000632963 1001_ $$aSabonis, Dziugas$$b0
000632963 245__ $$aTIR domains produce histidine-ADPR as an immune signal in bacteria
000632963 260__ $$aLondon [u.a.]$$bNature Publ. Group$$c2025
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000632963 520__ $$aToll/interleukin-1 receptor (TIR) domains are central components of pattern recognition immune proteins across all domains of life1,2. In bacteria and plants, TIR-domain proteins recognize pathogen invasion and then produce immune signalling molecules exclusively comprising nucleotide moieties2,3,4,5. Here we show that the TIR-domain protein of the type II Thoeris defence system in bacteria produces a unique signalling molecule comprising the amino acid histidine conjugated to ADP-ribose (His-ADPR). His-ADPR is generated in response to phage infection and activates the cognate Thoeris effector by binding a Macro domain located at the C terminus of the effector protein. By determining the crystal structure of a ligand-bound Macro domain, we describe the structural basis for His-ADPR and its recognition and show its role by biochemical and mutational analyses. Our analyses furthermore reveal a family of phage proteins that bind and sequester His-ADPR signalling molecules, enabling phages to evade TIR-mediated immunity. These data demonstrate diversity in bacterial TIR signalling and reveal a new class of TIR-derived immune signalling molecules that combine nucleotide and amino acid moieties.
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000632963 7001_ $$00000-0002-4288-0355$$aAvraham, Carmel$$b1
000632963 7001_ $$00000-0001-6298-7005$$aChang, Renee B.$$b2
000632963 7001_ $$aLu, Allen$$b3
000632963 7001_ $$00000-0002-5570-5804$$aHerbst, Ehud$$b4
000632963 7001_ $$aSilanskas, Arunas$$b5
000632963 7001_ $$aVilutis, Deividas$$b6
000632963 7001_ $$aLeavitt, Azita$$b7
000632963 7001_ $$aYirmiya, Erez$$b8
000632963 7001_ $$aToyoda, Hunter C.$$b9
000632963 7001_ $$aRuksenaite, Audrone$$b10
000632963 7001_ $$aZaremba, Mindaugas$$b11
000632963 7001_ $$00000-0001-7748-980X$$aOsterman, Ilya$$b12
000632963 7001_ $$00000-0002-2954-2503$$aAmitai, Gil$$b13
000632963 7001_ $$00000-0002-4943-733X$$aKranzusch, Philip J.$$b14$$eCorresponding author
000632963 7001_ $$00000-0002-3872-4982$$aSorek, Rotem$$b15$$eCorresponding author
000632963 7001_ $$aTamulaitiene, Giedre$$b16$$eCorresponding author
000632963 773__ $$0PERI:(DE-600)1413423-8$$a10.1038/s41586-025-08930-2$$gVol. 642, no. 8067, p. 467 - 473$$n8067$$p467 - 473$$tNature$$v642$$x0028-0836$$y2025
000632963 8564_ $$uhttps://www.nature.com/articles/s41586-025-08930-2#article-info
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