浙江大学张龙团队的一项最新研究提出了靶向关键二硫键调节RIG-I缩合和胞质RNA传感。2025年4月14日出版的《自然—细胞生物学》发表了这项成果。

在这里，该团队发现C864–C869介导的分子间二硫键形成是人类RIG-I激活的关键步骤，可以双向调节以控制先天免疫稳态。病毒刺激的C864-C869二硫键介导了SDS抗性RIG-I寡聚物的偶联，从而阻止了E3泛素连接酶MIB2对RIG-I的降解，并且是RIG-I进行液-液相分离以区隔下游信号体从而刺激I型干扰素信号传导所必需的。相应的C865S ‘敲入’在母基RIG-I中引起寡聚化缺陷和液-液相分离，抑制先天免疫，导致小鼠病毒载量和死亡率增加。利用非天然氨基酸生成共价C864-C869连接，并开发阻断C864-C869残基的干扰肽，双向调节RIG-I在人类疾病中的活性。这些发现提供了对RIG-I激活机制的深入见解，允许开发具有临床应用前景的方法。

据悉，维持先天免疫稳态对于预防感染和自身免疫性疾病至关重要，但缺乏有效的干预措施。

附：英文原文

Title: Targeting a key disulfide linkage to regulate RIG-I condensation and cytosolic RNA-sensing

Author: Wang, Bin, Wang, Yongqiang, Pan, Ting, Zhou, Lili, Ran, Yu, Zou, Jing, Yan, Xiaohua, Wen, Zhenke, Lin, Shixian, Ren, Aiming, Wang, Fangwei, Liu, Zhuang, Liu, Ting, Lu, Huasong, Yang, Bing, Zhou, Fangfang, Zhang, Long

Issue&Volume: 2025-04-14

Abstract: Maintaining innate immune homeostasis is critical for preventing infections and autoimmune diseases but effective interventions are lacking. Here we identified C864–C869-mediated intermolecular disulfide-linkage formation as a critical step for human RIG-I activation that can be bidirectionally regulated to control innate immune homeostasis. The viral-stimulated C864–C869 disulfide linkage mediates conjugation of an SDS-resistant RIG-I oligomer, which prevents RIG-I degradation by E3 ubiquitin-ligase MIB2 and is necessary for RIG-I to perform liquid–liquid phase separation to compartmentalize downstream signalsome, thereby stimulating type I interferon signalling. The corresponding C865S ‘knock-in’ caused an oligomerization defect and liquid–liquid phase separation in mouse RIG-I, which inhibited innate immunity, resulting in increased viral load and mortality in mice. Using unnatural amino acids to generate covalent C864–C869 linkage and the development of an interfering peptide to block C864–C869 residues, we bidirectionally regulated RIG-I activities in human diseases. These findings provide in-depth insights on mechanism of RIG-I activation, allowing for the development of methodologies that hold promising implications in clinics.

DOI: 10.1038/s41556-025-01646-5

Source: https://www.nature.com/articles/s41556-025-01646-5