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Activation of Thoeris antiviral system via SIR2 effector filament assembly

Author

Listed:
  • Giedre Tamulaitiene

    (Vilnius University)

  • Dziugas Sabonis

    (Vilnius University)

  • Giedrius Sasnauskas

    (Vilnius University)

  • Audrone Ruksenaite

    (Vilnius University)

  • Arunas Silanskas

    (Vilnius University)

  • Carmel Avraham

    (Weizmann Institute of Science)

  • Gal Ofir

    (Weizmann Institute of Science
    Max Planck Institute for Biology Tübingen)

  • Rotem Sorek

    (Weizmann Institute of Science)

  • Mindaugas Zaremba

    (Vilnius University)

  • Virginijus Siksnys

    (Vilnius University)

Abstract

To survive bacteriophage (phage) infections, bacteria developed numerous anti-phage defence systems1–7. Some of them (for example, type III CRISPR–Cas, CBASS, Pycsar and Thoeris) consist of two modules: a sensor responsible for infection recognition and an effector that stops viral replication by destroying key cellular components8–12. In the Thoeris system, a Toll/interleukin-1 receptor (TIR)-domain protein, ThsB, acts as a sensor that synthesizes an isomer of cyclic ADP ribose, 1′′−3′ glycocyclic ADP ribose (gcADPR), which is bound in the Smf/DprA-LOG (SLOG) domain of the ThsA effector and activates the silent information regulator 2 (SIR2)-domain-mediated hydrolysis of a key cell metabolite, NAD+ (refs. 12–14). Although the structure of ThsA has been solved15, the ThsA activation mechanism remained incompletely understood. Here we show that 1′′−3′ gcADPR, synthesized in vitro by the dimeric ThsB′ protein, binds to the ThsA SLOG domain, thereby activating ThsA by triggering helical filament assembly of ThsA tetramers. The cryogenic electron microscopy (cryo-EM) structure of activated ThsA revealed that filament assembly stabilizes the active conformation of the ThsA SIR2 domain, enabling rapid NAD+ depletion. Furthermore, we demonstrate that filament formation enables a switch-like response of ThsA to the 1′′−3′ gcADPR signal.

Suggested Citation

  • Giedre Tamulaitiene & Dziugas Sabonis & Giedrius Sasnauskas & Audrone Ruksenaite & Arunas Silanskas & Carmel Avraham & Gal Ofir & Rotem Sorek & Mindaugas Zaremba & Virginijus Siksnys, 2024. "Activation of Thoeris antiviral system via SIR2 effector filament assembly," Nature, Nature, vol. 627(8003), pages 431-436, March.
  • Handle: RePEc:nat:nature:v:627:y:2024:i:8003:d:10.1038_s41586-024-07092-x
    DOI: 10.1038/s41586-024-07092-x
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    Cited by:

    1. Xiangkai Zhen & Biao Zhou & Zihe Liu & Xurong Wang & Heyu Zhao & Shuxian Wu & Zekai Li & Jiamin liang & Wanyue Zhang & Qingjian Zhu & Jun He & Xiaoli Xiong & Songying Ouyang, 2024. "Mechanistic basis for the allosteric activation of NADase activity in the Sir2-HerA antiphage defense system," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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