近日，南开大学曹雪涛小组研究出内体自身RNA Rmrp参与TLR3二聚化以启动先天激活的分子特征。该研究于2025年9月8日发表于国际一流学术期刊《细胞研究》杂志上。

该课题组证明了内核体定位的自身RNA Rmrp在早期内核体中直接结合TLR3并诱导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-I相互作用。Rmrp - TLR3复合物的Cryo-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，扩展了他们对膜相关TLRs如何预二聚化的认识，并提出了亚细胞定位的自身RNA在增强先天激活方面的新功能。

据介绍，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。

附：英文原文

Title: Molecular characterization of endosomal self RNA Rmrp-engaged TLR3 dimerization to prime innate activation

Author: Zhang, Shikun, Li, Bo, Liu, Lun, Gong, Dongsheng, Zhang, Deyu, Liu, Fengjiang, Yang, Xiuna, Qin, Hua, Kong, Deling, Zhang, Shuyang, Rao, Zihe, Cao, Xuetao

Issue&Volume: 2025-09-08

Abstract: 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.

DOI: 10.1038/s41422-025-01178-5

Source: https://www.nature.com/articles/s41422-025-01178-5