Department of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China; and.
J Immunol. 2020 Apr 1;204(7):1904-1918. doi: 10.4049/jimmunol.1900305. Epub 2020 Feb 19.
IFN regulatory factor 3 (IRF3) is critical for the transcription of type I IFNs in defensing virus and promoting inflammatory responses. Although several kinds of posttranslational modifications have been identified to modulate the activity of IRF3, whether atypical ubiquitination participates in the function regulation, especially the DNA binding capacity of IRF3, is unknown. In this study, we found that the ovarian tumor domain containing deubiquitinase OTUD1 deubiquitinated IRF3 and attenuated its function. An atypical ubiquitination, K6-linked ubiquitination, was essential for the DNA binding capacity of IRF3 and subsequent induction of target genes. Mechanistically, OTUD1 cleaves the viral infection-induced K6-linked ubiquitination of IRF3, resulting in the disassociation of IRF3 from the promoter region of target genes, without affecting the protein stability, dimerization, and nuclear translocation of IRF3 after a viral infection. cells as well as mice produced more type I IFNs and proinflammatory cytokines after viral infection. mice were more resistant to lethal HSV-1 and VSV infection. Consistent with the former investigations that IRF3 promoted inflammatory responses in LPS-induced sepsis, mice were more susceptible to LPS stimulation. Taken together, our findings revealed that the DNA binding capacity of IRF3 in the innate immune signaling pathway was modulated by atypical K6-linked ubiquitination and deubiquitination process, which was regulated by the deubiquitinase OTUD1.
干扰素调节因子 3（IRF3）对于防御病毒和促进炎症反应中 I 型干扰素的转录至关重要。虽然已经确定了几种翻译后修饰来调节 IRF3 的活性，但是否存在非典型泛素化参与其功能调节，尤其是 IRF3 的 DNA 结合能力，目前尚不清楚。在这项研究中，我们发现卵巢肿瘤结构域包含去泛素化酶 OTUD1 可对 IRF3 去泛素化，从而减弱其功能。一种非典型泛素化，即 K6 连接的泛素化，对于 IRF3 的 DNA 结合能力和随后的靶基因诱导至关重要。从机制上讲，OTUD1 可切割病毒感染诱导的 IRF3 的 K6 连接泛素化，导致 IRF3 从靶基因的启动子区域解离，而不影响病毒感染后 IRF3 的蛋白稳定性、二聚化和核转位。OTUD1 缺失的细胞以及小鼠在病毒感染后产生更多的 I 型干扰素和促炎细胞因子。OTUD1 缺失的小鼠对致死性单纯疱疹病毒 1（HSV-1）和水疱性口炎病毒（VSV）感染更具抵抗力。与之前的研究结果一致，IRF3 在脂多糖（LPS）诱导的败血症中促进炎症反应，OTUD1 缺失的小鼠对 LPS 刺激更敏感。综上所述，我们的研究结果揭示了先天免疫信号通路中 IRF3 的 DNA 结合能力受非典型 K6 连接泛素化和去泛素化过程的调节，而这一过程受去泛素化酶 OTUD1 的调控。
