TIR signaling activates caspase-like immunity in bacteria

  • Science. 2025 Jan 31;387(6733):510-516. doi: 10.1126/science.adu2262.
François Rousset  #  1 ,  Ilya Osterman  #  1 ,  Tali Scherf  2 ,  Alla H Falkovich  2 ,  Azita Leavitt  1 ,  Gil Amitai  1 ,  Sapir Shir  1 ,  Sergey Malitsky  3 ,  Maxim Itkin  3 ,  Alon Savidor  4 ,  Rotem Sorek  1
Affiliations
  • 1. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
  • 2. Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, Israel.
  • 3. Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel.
  • 4. The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel.
  • # Contributed equally.
PMID: 39883761 DOI: 10.1126/science.adu2262
Abstract

Caspase family proteases and Toll/interleukin-1 receptor (TIR)-domain proteins have central roles in innate immunity and regulated cell death in humans. We describe a Bacterial immune system comprising both a caspase-like protease and a TIR-domain protein. We found that the TIR protein, once it recognizes phage invasion, produces the previously unknown immune signaling molecule adenosine 5'-diphosphate-cyclo[N7:1'']-ribose (N7-cADPR). This molecule specifically activates the Bacterial caspase-like protease, which then indiscriminately degrades cellular proteins to halt phage replication. The TIR-caspase defense system, which we denote as type IV Thoeris, is abundant in bacteria and efficiently protects against phage propagation. Our study highlights the diversity of TIR-produced immune signaling molecules and demonstrates that cell death regulated by proteases of the Caspase family is an ancient mechanism of innate immunity.

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