立陶宛维尔纽斯大学Virginijus Siksnys等研究人员合作揭示通过SIR2效应丝组装激活Thoeris抗病毒系统。2024年2月21日，《自然》杂志在线发表了这项成果。

研究人员表示，为了在细菌噬菌体（噬菌体）感染后存活下来，细菌开发出了许多抗噬菌体防御系统。其中一些系统（如III型CRISPR-Cas、CBASS、Pycsar和Thoeris）由两个模块组成：一个是负责识别感染的传感器，另一个是通过破坏关键细胞成分来阻止病毒复制的效应器。在Thoeris系统中，Toll/白细胞介素-1受体（TIR）域蛋白ThsB充当传感器，合成环状ADP核糖的异构体——1′′-3′糖环状ADP核糖（gcADPR）、它与ThsA效应器的Smf/DprA-LOG（SLOG）结构域结合，并激活沉默信息调节器2（SIR2）结构域介导的关键细胞代谢物NAD⁺的水解。虽然ThsA的结构已被解析，但ThsA的激活机制仍不完全清楚。

研究人员发现由二聚体ThsB′蛋白在体外合成的1′′-3′gcADPR可与ThsA的SLOG结构域结合，从而通过触发ThsA四聚体的螺旋丝组装激活ThsA。活化的ThsA的冷冻电镜（cryo-EM）结构显示，丝状组装稳定了ThsA SIR2结构域的活性构象，从而实现了NAD⁺的快速耗竭。此外，研究人员还证明，丝状结构的形成使ThsA能够对1′′-3′gcADPR信号做出类似开关的反应。

附：英文原文

Title: Activation of Thoeris antiviral system via SIR2 effector filament assembly

Author: Tamulaitiene, Giedre, Sabonis, Dziugas, Sasnauskas, Giedrius, Ruksenaite, Audrone, Silanskas, Arunas, Avraham, Carmel, Ofir, Gal, Sorek, Rotem, Zaremba, Mindaugas, Siksnys, Virginijus

Issue&Volume: 2024-02-21

Abstract: To survive bacteriophage (phage) infections, bacteria developed numerous anti-phage defence systems1,2,3,4,5,6,7. 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 components8,9,10,11,12. 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.12,13,14). 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.

DOI: 10.1038/s41586-024-07092-x

Source: https://www.nature.com/articles/s41586-024-07092-x