Jiang Xue, Xiao Yanping, Hou Wen, Yu Jingge, He Tian-Sheng, Xu Liang-Guo
College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi, China.
School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China.
J Cell Physiol. 2023 Oct;238(10):2348-2360. doi: 10.1002/jcp.31088. Epub 2023 Aug 10.
Innate immunity is the first line of defense against infections, which functions as a significant role in resisting pathogen invasion. Rapid immune response is initiated by pattern recognition receptors (PRRs) quickly distinguishing "self" and "non-self." Upon evolutionarily conserved pathogen-associated molecular pattern (PAMP) is recognized by PRRs, innate immune response against infection is triggered via an orchestration of molecular interaction, cytokines cascades, and immune cells. RIG-I plays a critical role in type I interferon (IFN-I) production by direct recognition of cytoplasmic double-stranded viral RNA. However, the activation mechanism of RIG-I is incompletely understood. In this study, we reported RNA-binding protein ZFP36 as a positive regulator of RIG-I-mediated IFN-I production. ZFP36 is a member of Zinc finger proteins (ZFPs) characterized by the zinc finger (ZnF) motif, which broadly involved gene transcription and signal transduction. However, its role in regulating antiviral innate immune signaling is still unclear. We found that ZFP36 associates with RIG-I and potentiates the FN-β production induced by SeV. Mechanistically, ZFP36 promotes K63-linked polyubiquitination of RIG-I, mostly at K154/K164/K172, thereby facilitating the activation of RIG-I during infection. While the mutant ZFP36 (C118S/C162S) failed to increase polyubiquitination of RIG-I and SeV induced FN-β. Our findings collectively demonstrated that ZFP36 acts as a positive regulator in antiviral innate immunity by targeting RIG-I for K63-linked ubiquitination, thus improving our understanding of the activation mechanism of RIG-I.
固有免疫是抵御感染的第一道防线，在抵抗病原体入侵中发挥着重要作用。模式识别受体（PRR）能快速区分“自身”和“非自身”，从而启动快速免疫反应。一旦PRR识别出进化上保守的病原体相关分子模式（PAMP），就会通过分子相互作用、细胞因子级联反应和免疫细胞的协同作用触发针对感染的固有免疫反应。维甲酸诱导基因I（RIG-I）通过直接识别细胞质双链病毒RNA在I型干扰素（IFN-I）产生中起关键作用。然而，RIG-I的激活机制尚未完全明确。在本研究中，我们报道了RNA结合蛋白ZFP36是RIG-I介导的IFN-I产生的正调控因子。ZFP36是锌指蛋白（ZFP）家族的成员，其特征在于锌指（ZnF）基序，广泛参与基因转录和信号转导。然而，其在调节抗病毒固有免疫信号传导中的作用仍不清楚。我们发现ZFP36与RIG-I相互作用，并增强了仙台病毒（SeV）诱导的IFN-β产生。从机制上讲，ZFP36促进RIG-I的K63连接的多聚泛素化，主要发生在K154/K164/K172位点，从而在感染过程中促进RIG-I的激活。而突变体ZFP36（C118S/C162S）未能增加RIG-I的多聚泛素化以及SeV诱导的IFN-β。我们的研究结果共同表明，ZFP36通过靶向RIG-I进行K63连接的泛素化，在抗病毒固有免疫中起正调控作用，从而增进了我们对RIG-I激活机制的理解。
