2. Academic Validation
  3. TIR domains produce histidine-ADPR as an immune signal in bacteria

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

  • Nature. 2025 Apr 30. doi: 10.1038/s41586-025-08930-2.
Dziugas Sabonis # 1,  Carmel Avraham # 2,  Renee B Chang # 3 4,  Allen Lu 3 4,  Ehud Herbst 2,  Arunas Silanskas 1,  Deividas Vilutis 1,  Azita Leavitt 2,  Erez Yirmiya 2,  Hunter C Toyoda 3 4,  Audrone Ruksenaite 1,  Mindaugas Zaremba 1,  Ilya Osterman 2,  Gil Amitai 2,  Philip J Kranzusch 5 6,  Rotem Sorek 7,  Giedre Tamulaitiene 8
Affiliations

Affiliations

  • 1 Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
  • 2 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
  • 3 Department of Microbiology, Harvard Medical School, Boston, MA, USA.
  • 4 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Department of Microbiology, Harvard Medical School, Boston, MA, USA. philip_kranzusch@dfci.harvard.edu.
  • 6 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. philip_kranzusch@dfci.harvard.edu.
  • 7 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. rotem.sorek@weizmann.ac.il.
  • 8 Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania. giedre.tamulaitiene@bti.vu.lt.
  • # Contributed equally.
PMID: 40307559 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 moieties2-5. 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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