UBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors.
UBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors.
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DOI：
10.1038/s41467-024-45141-1
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发表时间：
2024-01-26
影响因子：
16.6
通讯作者：
Wang, Penghua
中科院分区：
文献类型：
--
作者：
Yang, Duomeng;Geng, Tingting;Harrison, Andrew G.;Cahoon, Jason G.;Xing, Jian;Jiao, Baihai;Wang, Mark;Cheng, Chao;Hill, Robert E.;Wang, Huadong;Vella, Anthony T.;Cheng, Gong;Wang, Yanlin;Wang, Penghua
视黄酸诱导基因I （RIG-I）样受体（RLRs）是启动抗病毒免疫反应所必需的主要病毒RNA传感器。rlr受到严格的转录和翻译后调控，其中泛素化是最重要的调控之一。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，并鉴定出泛素蛋白连接酶E3组件n -识别蛋白5 （UBR5）是RLR转录的正调节因子。UBR5缺乏降低了对RNA病毒的抗病毒免疫反应，同时增加了病毒在原代细胞和小鼠中的复制。与野生型小鼠相比，Ubr5基因敲除小鼠更容易受到致命RNA病毒感染。在机制上，UBR5介导赖氨酸63连接的TRIM28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sumo化，从而解除了TRIM28对RLR转录的抑制作用。总之，UBR5能够快速上调RLR的表达，通过泛素化和去summoylated TRIM28来增强抗病毒免疫反应。RIG-I样受体感知RNA病毒并启动抗病毒免疫。在这里，作者筛选了375个确定的泛素连接酶，并提出UBR5通过解除trim28对RLR启动子施加的抑制来促进RLR转录。
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. The RIG-I like receptors sense RNA viruses and initiate antiviral immunity. Here the authors screen 375 definite ubiquitin ligases and propose UBR5 promotes RLR transcription by disengaging the TRIM28-imposed brake on the RLR promoters.
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