UBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors

• Published in: Nature communications 2024-01, Vol.15 (1), p.780-19, Article 780
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 13; 13/109; 14; 14/19; 38; 38/91; 42; 42/40; 631/250/255/2514; 631/250/262/2106; 631/250/262/2106/2518; 631/326/596/2553; 82/80; Animals; Antibiotics; Brakes; Cell Line; Cell lines; DEAD Box Protein 58 - genetics; DEAD Box Protein 58 - metabolism; Efficiency; Epigenetics; Genes; Humanities and Social Sciences; Immune response; Immunity; Immunity, Innate; Infections; Kinases; Ligands; Lysine; Medicine; Mice; multidisciplinary; Proteins; Receptors; Retinoic acid; Ribonucleic acid; RNA; RNA Viruses; Science; Science (multidisciplinary); SUMO protein; Transcription; Tripartite Motif Proteins - genetics; Tripartite Motif Proteins - metabolism; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Viral infections; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45141-1

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.