TIR domains produce histidine-ADPR as an immune signal in bacteria

IF 50.5 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Nature Pub Date : 2025-04-30 DOI:10.1038/s41586-025-08930-2
Dziugas Sabonis, Carmel Avraham, Renee B. Chang, Allen Lu, Ehud Herbst, Arunas Silanskas, Deividas Vilutis, Azita Leavitt, Erez Yirmiya, Hunter C. Toyoda, Audrone Ruksenaite, Mindaugas Zaremba, Ilya Osterman, Gil Amitai, Philip J. Kranzusch, Rotem Sorek, Giedre Tamulaitiene
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Abstract

Toll/interleukin-1 receptor (TIR) domains are central components of pattern recognition immune proteins across all domains of life1,2. In bacteria and plants, TIR-domain proteins recognize pathogen invasion and then produce immune signalling molecules exclusively comprising nucleotide moieties2–5. Here we show that the TIR-domain protein of the type II Thoeris defence system in bacteria produces a unique signalling molecule comprising the amino acid histidine conjugated to ADP-ribose (His-ADPR). His-ADPR is generated in response to phage infection and activates the cognate Thoeris effector by binding a Macro domain located at the C terminus of the effector protein. By determining the crystal structure of a ligand-bound Macro domain, we describe the structural basis for His-ADPR and its recognition and show its role by biochemical and mutational analyses. Our analyses furthermore reveal a family of phage proteins that bind and sequester His-ADPR signalling molecules, enabling phages to evade TIR-mediated immunity. These data demonstrate diversity in bacterial TIR signalling and reveal a new class of TIR-derived immune signalling molecules that combine nucleotide and amino acid moieties. In response to phage infection, the Toll/interleukin-1 receptor (TIR) domain protein ThsB of the type II Thoeris defence system produces histidine conjugated to ADP-ribose, which stimulates bacterial defence by interacting with the Macro domain of the ThsA membrane effector protein.

Abstract Image

Abstract Image

TIR结构域在细菌中产生组氨酸- adpr作为免疫信号
Toll/白细胞介素-1受体(interleukin-1 receptor, TIR)结构域是生命所有结构域模式识别免疫蛋白的核心组成部分1,2。在细菌和植物中,tir结构域蛋白识别病原体入侵,然后产生仅包含核苷酸片段2,3,4,5的免疫信号分子。在这里,我们展示了细菌II型Thoeris防御系统的tir结构域蛋白产生一种独特的信号分子,包括氨基酸组氨酸偶联adp核糖(His-ADPR)。His-ADPR是在噬菌体感染的反应中产生的,并通过结合位于效应蛋白C端的Macro结构域激活同源的Thoeris效应蛋白。通过确定配体结合的宏观结构域的晶体结构,我们描述了His-ADPR及其识别的结构基础,并通过生化和突变分析显示了它的作用。我们的分析进一步揭示了噬菌体蛋白家族结合和隔离His-ADPR信号分子,使噬菌体逃避tir介导的免疫。这些数据证明了细菌TIR信号的多样性,并揭示了一类新的TIR衍生免疫信号分子,它结合了核苷酸和氨基酸部分。
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来源期刊
Nature
Nature 综合性期刊-综合性期刊
CiteScore
90.00
自引率
1.20%
发文量
3652
审稿时长
3 months
期刊介绍: Nature is a prestigious international journal that publishes peer-reviewed research in various scientific and technological fields. The selection of articles is based on criteria such as originality, importance, interdisciplinary relevance, timeliness, accessibility, elegance, and surprising conclusions. In addition to showcasing significant scientific advances, Nature delivers rapid, authoritative, insightful news, and interpretation of current and upcoming trends impacting science, scientists, and the broader public. The journal serves a dual purpose: firstly, to promptly share noteworthy scientific advances and foster discussions among scientists, and secondly, to ensure the swift dissemination of scientific results globally, emphasizing their significance for knowledge, culture, and daily life.
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