TRAM促进不依赖Toll样受体的myddosome信号转导

TRAM促进不依赖Toll样受体的myddosome信号转导

作者： 小柯机器人 发布时间：2026/9/26 16:50:21

本期文章：《自然》：Online/在线发表

波士顿儿童医院和哈佛医学院Daniel Fisch团队近日取得一项新成果。经过不懈努力，他们发现了TRAM促进无toll样受体的心肌信号转导。2026年9月23日出版的《自然》杂志发表了这项成果。

在Toll样受体（TLR）信号转导通路中，活化的受体仅在被称为proto-myddosome的初始膜近端信号复合物中存在数分钟。Proto-myddosome迅速从TLR释放，自组装（即成熟）为富含酶的胞质超分子组织中心，称为myddosome。Myddosome诱导长达数小时的炎症基因表达。控制proto-myddosome释放的机制及其对信号转导的影响尚未明确。在此，研究人员鉴定了调控proto-myddosome成熟为无受体胞质myddosome过程的因子。通过对巨噬细胞的遗传筛选，研究人员鉴定出TRAM——此前被描述为控制不依赖MyD88的TLR信号——是myddosome组装的调控因子。利用生物化学、活细胞成像和重组蛋白活性重构，研究人员表明，质膜相关衔接蛋白TIRAP播种proto-myddosome，随后TRAM将MyD88从TLR-TIRAP复合物中解离，从而使myddosome成熟和下游信号转导得以进行。在TRAM缺失的情况下，MyD88无法从TLR-TIRAP复合物中解离，导致MyD88与下游信号酶发生异常且不稳定的相互作用。这些发现使研究人员能够鉴定出TRAM依赖的持久myddosome活性是TLR通路两个标志的决定因素：长达数小时的NF-κB激活和次级反应基因表达。胞质myddosome的化学解离破坏了体外和体内TLR刺激细胞已有的炎症活动。总之，这项工作确立了TRAM作为myddosome成熟和信号的调控因子，为无受体信号转导提供了分子基础。

附：英文原文

Title: TRAM promotes Toll-like-receptor-free myddosome signal transduction

Author: Fisch, Daniel, Ohri, Vaani, Anastasakou, Eleni, Wesemann, Lucia J., Choi, Joon H., Lindblad, Katherine E., Kagan, Jonathan C.

Issue&Volume: 2026-09-23

Abstract: In the Toll-like receptor (TLR) signal transduction pathways, activated receptors are present for mere minutes within the initial, membrane-proximal signalling complexes called proto-myddosomes1. Proto-myddosomes are rapidly released from TLRs to self-assemble (that is, mature) into enzyme-rich, cytosolic supramolecular organizing centres called myddosomes2,3,4. Myddosomes induce hours-long inflammatory gene expression5,6,7,8,9,10. The mechanism controlling proto-myddosome release and its effect on signal transduction are undefined. Here we identify factors that regulate the maturation process of proto-myddosomes into receptor-free cytosolic myddosomes11. Through a genetic screen in macrophages, we identify TRAM, which was previously described to control MyD88-independent TLR signalling, as a regulator of myddosome assembly. Using biochemistry, live-cell imaging and activity reconstitution with recombinant proteins, we show that the plasma-membrane-associated adapter TIRAP seeds proto-myddosomes12,13, after which TRAM dissociates MyD88 from the TLR–TIRAP complex to enable myddosome maturation and downstream signal transduction14,15,16,17,18,19. In the absence of TRAM, MyD88 cannot dissociate from the TLR–TIRAP complex, resulting in abnormal and unstable MyD88 interactions with downstream signalling enzymes. These findings enabled us to identify TRAM-dependent long-lasting myddosome activities as the determinant of two TLR pathway hallmarks: hours-long NF-κB activation20,21,22,23,24 and secondary response gene expression25,26,27. Chemical dissociation of cytosolic myddosomes disrupted existing inflammatory activities of TLR-stimulated cells in vitro and in vivo. Collectively, this work establishes TRAM as a regulator of myddosome maturation and signalling, providing the molecular basis for receptor-free signal transduction.

DOI: 10.1038/s41586-026-11052-y

Source: https://www.nature.com/articles/s41586-026-11052-y

主题：信号