USP5 inhibits anti-RNA viral innate immunity by deconjugating K48-linked unanchored and K63-linked anchored ubiquitin on IRF3

• Published in: PLoS pathogens 2025-01, Vol.21 (1), p.e1012843
• Main Authors: Qiao, Zigang, Li, Dapei, Zhang, Fan, Zhu, Jingfei, Liu, Siying, Bai, Xue, Yao, Haiping, Chen, Zhengrong, Yan, Yongdong, Xu, Xiulong, Ma, Feng
• Format: Article
• Language: English
• ISSN: 1553-7374; 1553-7374
• DOI: 10.1371/journal.ppat.1012843

Interferon regulatory factor 3 (IRF3) is a central hub transcription factor that controls host antiviral innate immunity. The expression and function of IRF3 are tightly regulated by the post-translational modifications. However, it is unknown whether unanchored ubiquitination and deubiquitination of IRF3 involve modulating antiviral innate immunity against RNA viruses. Here, we find that USP5, a deubiquitinase (DUB) regulating unanchored polyubiquitin, is downregulated during host anti-RNA viral innate immunity in a type I interferon (IFN-I) receptor (IFNAR)-dependent manner. USP5 is further identified to inhibit IRF3-triggered antiviral immune responses through its DUB enzyme activity. K48-linked unanchored ubiquitin promotes IRF3-driven transcription of IFN-β and induction of IFN-stimulated genes (ISGs) in a dose-dependent manner. USP5 simultaneously removes both K48-linked unanchored and K63-linked anchored polyubiquitin chains on IRF3. Our study not only provides evidence that unanchored ubiquitin regulates anti-RNA viral innate immunity but also proposes a novel mechanism for DUB-controlled IRF3 activation, suggesting that USP5 is a potential target for the treatment of RNA viruses infectious diseases.