内体自身RNA rmrp参与TLR3二聚化以启动先天激活的分子特征。

IF 25.9 1区 生物学 Q1 CELL BIOLOGY
Shikun Zhang,Bo Li,Lun Liu,Dongsheng Gong,Deyu Zhang,Fengjiang Liu,Xiuna Yang,Hua Qin,Deling Kong,Shuyang Zhang,Zihe Rao,Xuetao Cao
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引用次数: 0

摘要

内核体定位RNA传感器toll样受体3 (TLR3)的预二聚体是其先天识别所必需的,但TLR3的预二聚体是如何形成的,以及如何精确地为先天激活启动尚不清楚。在此,我们证明了内核体定位的自身RNA Rmrp直接与TLR3结合并在早期内核体中诱导TLR3二聚化,但在稳态条件下不与内核体定位的TLR7、TLR8、TLR9或细胞质RNA传感器rig - 1相互作用。Rmrp-TLR3复合物的cro - em结构揭示了Rmrp参与的TLR3二聚体的一种新的重叠构象,这与dsRNA的激活机制不同,Rmrp 3'端的特定结构特征对于其与TLR3的功能相互作用至关重要。此外,TLR3的K42残基对于Rmrp的结合和随后的二聚化是必不可少的。Rmrp在内体酸化后与TLR3分离,产生成熟的TLR3二聚体,为先天识别和激活做好准备。在体外和体内研究中,髓细胞Rmrp缺失可降低TLR3二聚体并减弱TLR3介导的抗甲型流感抗病毒反应。这些发现阐明了自身RNA rmrp引发的TLR3二聚化的结构模式,并准备好在内体膜上进行有效的先天识别,扩展了我们对膜相关TLRs如何预二聚化的认识,并提示亚细胞定位的自身RNA在增强先天激活方面的新功能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Molecular characterization of endosomal self RNA Rmrp-engaged TLR3 dimerization to prime innate activation.
The pre-dimerization of endosome-localized RNA sensor Toll-like receptor 3 (TLR3) is required for its innate recognition, yet how TLR3 pre-dimers are formed and precisely primed for innate activation remains unclear. Here, we demonstrate that endosome-localized self RNA Rmrp directly binds to TLR3 and induces TLR3 dimerization in the early endosome but does not interact with endosome-localized TLR7, TLR8, TLR9 or cytoplasmic RNA sensor RIG-I under homeostatic conditions. Cryo-EM structure of Rmrp-TLR3 complex reveals a novel lapped conformation of TLR3 dimer engaged by Rmrp, which is distinct from the activation mechanism by dsRNA and the specific structural feature at the 3'-end of Rmrp is critical for its functional interaction with TLR3. Furthermore, K42 residue of TLR3 is essential for binding to Rmrp and subsequent dimerization. Rmrp dissociates from TLR3 following endosomal acidification, generating a matured TLR3 dimer which is primed for innate recognition and activation. Myeloid-cell deficiency of Rmrp reduces TLR3 dimerization and attenuates TLR3-mediated antiviral responses against influenza A both in vitro and in vivo. These findings elucidate the structural mode of self RNA Rmrp-primed TLR3 dimerization and ready for efficient innate recognition on endosomal membrane, extending our knowledge of how membrane-associated TLRs pre-dimerize and suggesting a new function of subcellular localized self RNAs in empowering innate activation.
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来源期刊
Cell Research
Cell Research 生物-细胞生物学
CiteScore
53.90
自引率
0.70%
发文量
2420
审稿时长
2.3 months
期刊介绍: Cell Research (CR) is an international journal published by Springer Nature in partnership with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). It focuses on publishing original research articles and reviews in various areas of life sciences, particularly those related to molecular and cell biology. The journal covers a broad range of topics including cell growth, differentiation, and apoptosis; signal transduction; stem cell biology and development; chromatin, epigenetics, and transcription; RNA biology; structural and molecular biology; cancer biology and metabolism; immunity and molecular pathogenesis; molecular and cellular neuroscience; plant molecular and cell biology; and omics, system biology, and synthetic biology. CR is recognized as China's best international journal in life sciences and is part of Springer Nature's prestigious family of Molecular Cell Biology journals.
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