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<p>Triggering immune response through generation of signal molecules is a common immune strategy across all domains of life. In the bacterial type IV Thoeris anti-phage system, a Toll/interleukin-1 receptor (TIR)-domain protein produces adenosine 5’-diphosphate-cyclo[N7:1”]-ribose (N7-cADPR) as the immune signal to activate a Caspase-like effector. Here, we identified an inhibitor of type IV Thoeris through a phage mating assay that allows a sensitive phage to acquire anti-defense genes from related resistant phages. The inhibitor (hereafter TadIV-1) functions as a sponge that sequesters the N7-cADPR signal to inhibit Caspase activation. Structural analyses of TadIV-1 indicate a distinctive signal binding mechanism, wherein the binding pocket comprises its N-terminal flexible loop. In addition, phages lacking TadIV-1 can escape type IV Thoeris sensing through mutation in the capsid vertex protein. Collectively, this work expands the phage anti-defense arsenal with a unique immune signal sequestration mechanism and provides insights into phage invasion recognition mechanism of type IV Thoeris.</p>

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A phage-encoded sponge protein suppresses bacterial TIR-Caspase immune signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月13日

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  • Yu Chen,
  • Linlin Wei,
  • Zhenhao Han,
  • Ruiliang Zhao,
  • Zhifeng Zeng,
  • Yanqiu Liu,
  • Piaoran Zhang,
  • Keyi Tan,
  • Yue Fan,
  • Long Sheng,
  • Hao Wang,
  • Rafael Pinilla-Redondo,
  • Yue Feng,
  • Wenyuan Han

摘要

Triggering immune response through generation of signal molecules is a common immune strategy across all domains of life. In the bacterial type IV Thoeris anti-phage system, a Toll/interleukin-1 receptor (TIR)-domain protein produces adenosine 5’-diphosphate-cyclo[N7:1”]-ribose (N7-cADPR) as the immune signal to activate a Caspase-like effector. Here, we identified an inhibitor of type IV Thoeris through a phage mating assay that allows a sensitive phage to acquire anti-defense genes from related resistant phages. The inhibitor (hereafter TadIV-1) functions as a sponge that sequesters the N7-cADPR signal to inhibit Caspase activation. Structural analyses of TadIV-1 indicate a distinctive signal binding mechanism, wherein the binding pocket comprises its N-terminal flexible loop. In addition, phages lacking TadIV-1 can escape type IV Thoeris sensing through mutation in the capsid vertex protein. Collectively, this work expands the phage anti-defense arsenal with a unique immune signal sequestration mechanism and provides insights into phage invasion recognition mechanism of type IV Thoeris.