Activation of Thoeris antiviral system via SIR2 effector filament assembly

Giedre Tamulaitiene (), Dziugas Sabonis, Giedrius Sasnauskas, Audrone Ruksenaite, Arunas Silanskas, Carmel Avraham, Gal Ofir, Rotem Sorek, Mindaugas Zaremba () and Virginijus Siksnys ()
Additional contact information
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
Rotem Sorek: Weizmann Institute of Science
Mindaugas Zaremba: Vilnius University
Virginijus Siksnys: Vilnius University

Nature, 2024, vol. 627, issue 8003, 431-436

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07092-x

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