The Retinoic acid-Inducible Gene I (RIG-I) like receptors (RLRs) are the major viral RNA sensors essential for the initiation of antiviral immune responses. RLRs are subjected to stringent transcriptional and posttranslational regulations, of which ubiquitination is one of the most important. However, the role of ubiquitination in RLR transcription is unknown. Here, we screen 375 definite ubiquitin ligase knockout cell lines and identify Ubiquitin Protein Ligase E3 Component N-Recognin 5 (UBR5) as a positive regulator of RLR transcription. UBR5 deficiency reduces antiviral immune responses to RNA viruses, while increases viral replication in primary cells and mice. Ubr5 knockout mice are more susceptible to lethal RNA virus infection than wild type littermates. Mechanistically, UBR5 mediates the Lysine 63-linked ubiquitination of Tripartite Motif Protein 28 (TRIM28), an epigenetic repressor of RLRs. This modification prevents intramolecular SUMOylation of TRIM28, thus disengages the TRIM28-imposed brake on RLR transcription. In sum, UBR5 enables rapid upregulation of RLR expression to boost antiviral immune responses by ubiquitinating and de-SUMOylating TRIM28.

视黄酸诱导基因 I （RIG-I） 样受体 （RLR） 是启动抗病毒免疫反应所必需的主要病毒 RNA 传感器。RLR 受严格的转录和翻译后调节，其中泛素化是最重要的调节之一。然而，泛素化在 RLR 转录中的作用尚不清楚。在这里，我们筛选了 375 个明确的泛素连接酶敲除细胞系，并将泛素蛋白连接酶 E3 组分 N-识别蛋白 5 （UBR5） 鉴定为 RLR 转录的正调节因子。UBR5 缺陷会降低对 RNA 病毒的抗病毒免疫反应，同时增加病毒在原代细胞和小鼠中的复制。Ubr5 敲除小鼠比野生型同窝小鼠更容易受到致命的 RNA 病毒感染。从机制上讲，UBR5 介导三联基序蛋白 28 （TRIM28） 的赖氨酸 63 连接泛素化，TRIM28 是 RLR 的表观遗传抑制因子。这种修饰阻止了 TRIM28 的分子内 SUMOylation，从而解除了 TRIM28 对 RLR 转录施加的制动。总之，UBR5 能够快速上调 RLR 表达，通过泛素化和去 SUMO 化 TRIM28 来增强抗病毒免疫反应。