8BTN

Activation of Thoeris antiviral system via SIR2 effector filament assembly.

(2024) Nature 627: 431-436

• PubMed: 38383786 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1038/s41586-024-07092-x
• Primary Citation of Related Structures:  
  8BTN, 8BTO, 8BTP


• PubMed Abstract: 
  

  To survive bacteriophage (phage) infections, bacteria developed numerous anti-phage defence systems ^1-7 . 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 components ^8-12 . 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 solved ¹⁵ , 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.

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Organizational Affiliation: 

Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania. giedre.tamulaitiene@bti.vu.lt.