Chen Xiangjie, Xu Ying, Tu Wenhui, Huang Fan, Zuo Yibo, Zhang Hong-Guang, Jin Lincong, Feng Qian, Ren Tengfei, He Jiuyi, Miao Ying, Yuan Yukang, Zhao Qian, Liu Jiapeng, Zhang Renxia, Zhu Li, Qian Feng, Zhu Chuanwu, Zheng Hui, Wang Jun
Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
Department of Intensive Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.
Immunology. 2021 Jul;163(3):278-292. doi: 10.1111/imm.13315. Epub 2021 Feb 22.
Interferon regulatory factor 3 (IRF3) is a critical transcription factor for inducing production of type I interferons (IFN-I) and regulating host antiviral response. Although IRF3 activation during viral infection has been extensively studied, the inhibitory regulation of IRF3 remains largely unexplored. Here, we revealed that Midline-1 (MID1) is a ubiquitin E3 ligase of IRF3 that plays essential roles in regulating the production of IFN-I. We found that MID1 physically interacts with IRF3 and downregulates IRF3 protein levels. Next, we demonstrated that MID1 can induce K48-linked polyubiquitination of IRF3, thus lowing the protein stability of IRF3. Our further studies identified Lys313 as a major ubiquitin acceptor lysine of IRF3 induced by MID1. Finally, MID1-mediated ubiquitination and degradation of IRF3 restrict IFN-I production and cellular antiviral response. This study uncovers a role of MID1 in regulating innate antiviral immunity and may provide a potential target for enhancing host antiviral activity.
干扰素调节因子3（IRF3）是诱导I型干扰素（IFN-I）产生和调节宿主抗病毒反应的关键转录因子。尽管病毒感染期间IRF3的激活已得到广泛研究，但IRF3的抑制性调节在很大程度上仍未被探索。在此，我们揭示了中线-1（MID1）是IRF3的一种泛素E3连接酶，在调节IFN-I的产生中起重要作用。我们发现MID1与IRF3发生物理相互作用并下调IRF3蛋白水平。接下来，我们证明MID1可诱导IRF3的K48连接的多聚泛素化，从而降低IRF3的蛋白质稳定性。我们的进一步研究确定赖氨酸313是MID1诱导的IRF3的主要泛素接受赖氨酸。最后，MID1介导的IRF3泛素化和降解限制了IFN-I的产生和细胞抗病毒反应。这项研究揭示了MID1在调节先天性抗病毒免疫中的作用，并可能为增强宿主抗病毒活性提供一个潜在靶点。
