Huang Wenji, Wang Yafang, Ji Ning, Xiao Hehe, Chen Kangyong, Guo Jiahong, Feng Jianhua, Mustafa Nageen, Wang Junya, Feng Hao, Zou Jun
Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China.
Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, China.
J Immunol. 2025 Jul 1;214(7):1552-1565. doi: 10.1093/jimmun/vkaf064.
A balanced IFN response, tightly regulated at multiple levels, is essential for host defense against viral infection. Tripartite motif-containing (TRIM) proteins are a large group of E3 ubiquitin ligases, and have been shown to be involved in the regulation of IFN response. However, the regulatory functions of individual TRIM proteins remain controversial. Here, we show that a virus-inducible TRIM2 homolog acts as a negative regulator for IFN production in zebrafish. Zebrafish Trim2a was upregulated in response to spring viremia of carp virus (SVCV) infection, and knockout of Trim2a significantly increased the expression of antiviral genes, leading to enhanced resistance to SVCV. Overexpression of Trim2a resulted in pronounced ubiquitination of IFN regulatory factor 3 (IRF3) via K11, K27, K29, and K48, promoting IRF3 degradation and stability of SVCV phosphoprotein to favor viral replication. Moreover, TRIM2a induced ubiquitination of autophagic cargo receptor p62, which then interacted with IRF3, instigating IRF3 degradation. Further, the inhibitory effects of TRIM2a on IFN production were also observed in human HEK293 cells, suggesting that the regulatory functions of TRIM2 are likely to be conserved during evolution. Collectively, our findings demonstrate that TRIM2a is a negative regulator of IFN production, and could serve as a potential target to dampen exacerbated IFN response triggered by aberrant activation of retinoic acid-inducible gene 1 (RIG-I)-like receptors. Our study provides insights into a previously uncharacterized role of TRIM2 in the regulation of IFN signaling.
在多个水平受到严格调控的平衡的干扰素反应，对于宿主抵御病毒感染至关重要。含三联基序的（TRIM）蛋白是一大类E3泛素连接酶，已被证明参与干扰素反应的调控。然而，单个TRIM蛋白的调控功能仍存在争议。在此，我们表明一种病毒诱导的TRIM2同源物在斑马鱼中作为干扰素产生的负调节因子发挥作用。斑马鱼Trim2a在鲤春病毒血症病毒（SVCV）感染后上调，敲除Trim2a显著增加抗病毒基因的表达，从而增强对SVCV的抗性。Trim2a的过表达导致干扰素调节因子3（IRF3）通过K11、K27、K29和K48发生明显的泛素化，促进IRF3降解以及SVCV磷蛋白的稳定性，有利于病毒复制。此外，TRIM2a诱导自噬货物受体p62的泛素化，然后p62与IRF3相互作用，促使IRF3降解。此外，在人HEK293细胞中也观察到TRIM2a对干扰素产生的抑制作用，这表明TRIM2的调控功能在进化过程中可能是保守的。总的来说，我们的研究结果表明TRIM2a是干扰素产生的负调节因子，并且可以作为一个潜在靶点来抑制由视黄酸诱导基因1（RIG-I）样受体异常激活引发的过度干扰素反应。我们的研究为TRIM2 在干扰素信号调控中以前未被描述的作用提供了见解。
