Activation of Thoeris antiviral system via SIR2 effector filament assembly

• 成果类型: Article
• 署名作者: Tamulaitiene, Giedre; Sabonis, Dziugas; Sasnauskas, Giedrius; Ruksenaite, Audrone; Silanskas, Arunas; Avraham, Carmel; Ofir, Gal; Sorek, Rotem; Zaremba, Mindaugas; Siksnys, Virginijus
• 署名单位: Vilnius University; Weizmann Institute of Science
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5074
• DOI: 10.1038/s41586-024-07092-x
• 发表日期: 2024-03-14
• 页码: 431-+
• 关键词: protect bacteria; immunity

摘要

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.