美国哈佛大学Jonathan C. Kagan研究小组揭示内源性Toll样受体信号通路的分子定义。2024年7月3日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员表示，先天免疫模式识别受体，如Toll样受体（TLR），是感染免疫反应的关键介质，对于理解健康和疾病至关重要。微生物检测后，这些受体激活涉及IκB激酶、丝裂原活化蛋白激酶、泛素连接酶和其他适配蛋白的炎症信号传导途径。然而，连接TLR途径中蛋白质的机制尚未明确。

为阐明TLR途径活动，研究人员设计了可以进行显微镜和蛋白质组分析的内源性myddosome成分的巨噬细胞。研究发现，myddosome与激活的TLR形成短暂接触，且无TLR的myddosome在24小时内在大小、数量和组成上动态变化。超分辨率显微镜分析显示，在大多数myddosome中，MyD88形成桶状结构，作为效应蛋白招募的支架。

蛋白质组分析表明，myddosome包含在TLR途径所有阶段起作用并调节所有效应反应的蛋白质，遗传分析定义了这些效应模块之间的上位关系。在感染单核细胞增生李斯特菌的细胞中可以明显看到myddosome的组装，但这些细菌在细胞间传播过程中逃避了myddosome的组装和TLR信号传导。基于这些发现，研究人员提出整个TLR信号传导途径是从myddosome内执行的。

附：英文原文

Title: Molecular definition of the endogenous Toll-like receptor signalling pathways

Author: Fisch, Daniel, Zhang, Tian, Sun, He, Ma, Weiyi, Tan, Yunhao, Gygi, Steven P., Higgins, Darren E., Kagan, Jonathan C.

Issue&Volume: 2024-07-03

Abstract: Innate immune pattern recognition receptors, such as the Toll-like receptors (TLRs), are key mediators of the immune response to infection and central to our understanding of health and disease1. After microbial detection, these receptors activate inflammatory signal transduction pathways that involve IκB kinases, mitogen-activated protein kinases, ubiquitin ligases and other adaptor proteins. The mechanisms that connect the proteins in the TLR pathways are poorly defined. To delineate TLR pathway activities, we engineered macrophages to enable microscopy and proteomic analysis of the endogenous myddosome constituent MyD88. We found that myddosomes form transient contacts with activated TLRs and that TLR-free myddosomes are dynamic in size, number and composition over the course of 24h. Analysis using super-resolution microscopy revealed that, within most myddosomes, MyD88 forms barrel-like structures that function as scaffolds for effector protein recruitment. Proteomic analysis demonstrated that myddosomes contain proteins that act at all stages and regulate all effector responses of the TLR pathways, and genetic analysis defined the epistatic relationship between these effector modules. Myddosome assembly was evident in cells infected with Listeria monocytogenes, but these bacteria evaded myddosome assembly and TLR signalling during cell-to-cell spread. On the basis of these findings, we propose that the entire TLR signalling pathway is executed from within the myddosome.

DOI: 10.1038/s41586-024-07614-7

Source: https://www.nature.com/articles/s41586-024-07614-7