小柯机器人

美国哈佛医学院Philip J. Kranzusch、Sichen Shao等研究人员合作揭示活化的细菌TIR-STING细丝复合物的冷冻电镜结构。2022年7月20日，《自然》杂志在线发表了这项成果。

研究人员使用冷冻电镜确定了来自粪肠球菌环状寡核苷酸抗噬菌体信号系统（CBASS）防御操作子的，活性Toll/白细胞介素-1受体（TIR）-STING细丝复合物结构。细菌TIR-STING细丝的形成是由STING界面驱动的，这些界面在高亲和力识别同源的环状二核苷酸信号c-di-GMP时变得暴露。重复的二聚体STING单元通过表面接口横向堆叠，这对人类STING四聚体的形成和哺乳动物的下游免疫信号传导也至关重要。

活化细菌TIR-STING结构显示了进一步的跨丝接触，这些接触支撑着装配，并协调包装相关的TIR NAD酶效应域，从而驱动NAD⁺水解。STING界面和跨丝接触对体内细胞生长停滞至关重要，并揭示了一种逐步激活的机制，即STING细丝的组装是后续效应子激活的必要条件。这些研究结果确定了原核生物抗病毒信号中STING细丝形成的结构基础。

据了解，STING是一种抗病毒信号蛋白，在动物的先天免疫和原核生物的噬菌体防御中都是广泛保守的。STING的激活需要其通过与环状二核苷酸的结合组装成一个寡聚丝状结构，但STING丝状组装和延伸的分子基础仍然未知。

附：英文原文

Title: Cryo-EM structure of an active bacterial TIR–STING filament complex

Author: Morehouse, Benjamin R., Yip, Matthew C. J., Keszei, Alexander F. A., McNamara-Bordewick, Nora K., Shao, Sichen, Kranzusch, Philip J.

Issue&Volume: 2022-07-20

Abstract: Stimulator of interferon genes (STING) is an antiviral signalling protein that is broadly conserved in both innate immunity in animals and phage defence in prokaryotes1,2,3,4. Activation of STING requires its assembly into an oligomeric filament structure through binding of a cyclic dinucleotide4,5,6,7,8,9,10,11,12,13, but the molecular basis of STING filament assembly and extension remains unknown. Here we use cryogenic electron microscopy to determine the structure of the active Toll/interleukin-1 receptor (TIR)–STING filament complex from a Sphingobacterium faecium cyclic-oligonucleotide-based antiphage signalling system (CBASS) defence operon. Bacterial TIR–STING filament formation is driven by STING interfaces that become exposed on high-affinity recognition of the cognate cyclic dinucleotide signal c-di-GMP. Repeating dimeric STING units stack laterally head-to-head through surface interfaces, which are also essential for human STING tetramer formation and downstream immune signalling in mammals5. The active bacterial TIR–STING structure reveals further cross-filament contacts that brace the assembly and coordinate packing of the associated TIR NADase effector domains at the base of the filament to drive NAD+ hydrolysis. STING interface and cross-filament contacts are essential for cell growth arrest in vivo and reveal a stepwise mechanism of activation whereby STING filament assembly is required for subsequent effector activation. Our results define the structural basis of STING filament formation in prokaryotic antiviral signalling.

DOI: 10.1038/s41586-022-04999-1

Source: https://www.nature.com/articles/s41586-022-04999-1

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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