Prolonged activation of interferon–STAT1 signaling is closely related to inflammatory autoimmune disorders, and therefore the identification of negative regulators of these pathways is important. Through high-content screening of 115 mouse RING-domain E3 ligases, we identified the E3 ubiquitin ligase RNF2 as a potent inhibitor of interferon-dependent antiviral responses. RNF2 deficiency substantially enhanced interferon-stimulated gene (ISG) expression and antiviral responses. Mechanistically, nuclear RNF2 directly bound to STAT1 after interferon stimulation and increased K33-linked polyubiquitination of the DNA-binding domain of STAT1 at position K379, in addition to promoting the disassociation of STAT1/STAT2 from DNA and consequently suppressing ISG transcription. Our study provides insight into the regulation of interferon-dependent responses via a previously unrecognized post-translational modification of STAT1 in the nucleus.

中文翻译：

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核RNF2通过促进K33连接的STAT1与DNA的解离而抑制干扰素功能

干扰素–STAT1信号转导的长时间激活与炎性自身免疫性疾病密切相关，因此，鉴定这些途径的负调控因子非常重要。通过高含量筛选的115小鼠RING域E3连接酶，我们确定E3泛素连接酶RNF2是干扰素依赖性抗病毒应答的有效抑制剂。RNF2缺乏症大大增强了干扰素刺激基因（ISG）的表达和抗病毒反应。从机制上讲，核RNF2在干扰素刺激后直接结合到STAT1上，并增加了STAT1与DNA的结合域在K379位点的K33连锁多泛素化作用，此外还促进了STAT1 / STAT2与DNA的解离并因此抑制了ISG的转录。