Hou Jinxiu, Zheng Shengnan, Zhang Xuejing, Zhuang Mengwei, Zhao Xianghe, Deng Jian, Yang Huiyu, Xia Xiaojing, Gao Chengjiang, Wang Pei-Hui, Zheng Yi
Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China.
Key Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Cell Rep. 2025 Mar 25;44(3):115348. doi: 10.1016/j.celrep.2025.115348. Epub 2025 Feb 27.
Mitochondrial antiviral signaling protein (MAVS) is a central adaptor protein in retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling against RNA viral infection. Posttranslational modifications (PTMs) play a critical role in modulating the activity of MAVS. However, how phase separation regulates the PTMs to fine-tune MAVS activation remains to be elucidated. In this study, we identify Toll-interacting protein (TOLLIP) as a negative regulator of RLR signaling. A deficiency of TOLLIP leads to an enhanced type I interferon response upon RNA viral infection. Mice with the deletion of TOLLIP are more resistant to lethal vesicular stomatitis virus (VSV) infection than wild-type counterparts. Mechanistically, TOLLIP forms condensates that rely on its intrinsically disordered region (IDR). TOLLIP condensates interact with SENP1, promote the aggregation of SENP1, and enhance the interaction between SENP1 and MAVS, consequently leading to deSUMOylation and less aggregation of MAVS. Overall, our study reveals the critical role of TOLLIP condensation in regulating the activation of MAVS, emphasizing the complexity of MAVS activity modulation.
线粒体抗病毒信号蛋白（MAVS）是维甲酸诱导基因I（RIG-I）样受体（RLR）信号通路中对抗RNA病毒感染的核心衔接蛋白。翻译后修饰（PTM）在调节MAVS活性方面发挥着关键作用。然而，相分离如何调节PTM以微调MAVS激活仍有待阐明。在本研究中，我们鉴定出Toll相互作用蛋白（TOLLIP）是RLR信号通路的负调节因子。TOLLIP的缺失导致RNA病毒感染后I型干扰素反应增强。与野生型小鼠相比，缺失TOLLIP的小鼠对致死性水泡性口炎病毒（VSV）感染更具抵抗力。从机制上讲，TOLLIP形成依赖其内在无序区域（IDR）的凝聚物。TOLLIP凝聚物与SENP1相互作用，促进SENP1的聚集，并增强SENP1与MAVS之间的相互作用，从而导致MAVS去SUMO化和聚集减少。总体而言，我们的研究揭示了TOLLIP凝聚在调节MAVS激活中的关键作用，强调了MAVS活性调节的复杂性。
