AI Insight
This study identifies USP39, a ubiquitin-specific peptidase, as a positive regulator of innate antiviral immunity operating through two distinct mechanisms. USP39 enhances RIG-I protein levels by promoting the splicing and maturation of pre-RIG-I mRNA, while simultaneously stabilizing STING protein by removing K48-linked polyubiquitin chains at the K288 residue, thereby preventing its degradation. Both in vitro and in vivo experiments confirmed that USP39 deficiency increases susceptibility to RNA viruses such as VSV and H1N1 PR8, as well as the DNA virus HSV-1, whereas USP39 overexpression strengthens antiviral defense and type I interferon production.
Why it matters
USP39 represents a potential therapeutic target for antiviral interventions, as modulating its activity could enhance innate immune responses against a broad range of both RNA and DNA viral infections. Understanding how a single factor controls two major antiviral signaling pathways simultaneously may help guide the development of more broadly effective antiviral strategies.
by Jiazheng Quan, Xibao Zhao, Shaoying Chen, Hongrui Li, Wei Chen, Qianqian Di, Xunwei Li, Jiajing Zhao, Han Wu, Jin Chen, Yue Xiao, Zherui Wu, Weilin Chen
RIG-I and STING are critical for mediating the RIG-I and cGAS-STING signaling pathways that guard against viral infection. Here, we report that ubiquitin-specific peptidase 39 (USP39) positively regulates the RIG-I and cGAS-STING pathways to induce antiviral innate immunity in vitro and in vivo. The USP39 deficiency impaired the antiviral immune response of macrophages, leading to low type I IFNs expression, and high RNA and (e.g., VSV, H1N1 PR8) DNA virus (e.g., HSV-1) replication. Moreover, USP39-deficient mice were more sensitive to VSV or HSV-1 infection than control mice. Conversely, USP39 overexpression promoted the antiviral immune response. Mechanistically, we found that USP39 regulates RIG-I protein expression by promoting pre-RIG-I mRNA splicing and maturation. In addition, we also revealed that USP39 interacts with and stabilizes STING protein by deubiquitinating K48-linked polyubiquitin of STING at K288. These data show that USP39 positively regulates RNA and DNA-virus-induced RIG-I and cGAS-STING signaling, respectively, by promoting post-transcriptional control of RIG-I and stabilization of STING. These data provide new insights and potential therapeutic targets to control viral infections.