Dong Wenjing, Xie Meina, Li Wenxin, Xu Tianjun, Sun Yuena
Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China.
Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China; Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, China; Marine Biomedical Science and Technology Innovation Platform of Lin-gang Special Area, Shanghai, China.
Fish Shellfish Immunol. 2025 Nov;166:110578. doi: 10.1016/j.fsi.2025.110578. Epub 2025 Jul 21.
Ubiquitination, an essential post-translational regulatory mechanism, is primarily controlled by E3 ubiquitin ligases that dictate substrate specificity. Following microbial invasion, the innate immune defense mechanism is rapidly activated, wherein transforming growth factor-β-activated kinase 1 (MAP3K7/TAK1), a pivotal node in innate immune signaling, is tightly regulated by E3 ubiquitin ligases that dictate its stability and activity. Among these, Ring Finger Protein 34 (RNF34), a member of the E3 ligase family, has a role in regulating innate immunity in teleost fish that remains uncharacterized. In this study, we systematically investigate how RNF34 modulates this process using miiuy croaker (Miichthys miiuy). Siniperca chuatsi rhabdovirus (SCRV) infection significantly upregulates RNF34 expression, thereby promoting viral replication and suppressing transcription of key antiviral genes, including pro-inflammatory cytokines (IL-8, IL-1β) and interferon-stimulated genes (ISG15, MX1, Viperin). In luciferase reporter assays, this inhibitory effect was associated with RNF34-mediated suppression of the NF-κB/IRF3 signaling pathway. Western blot analysis revealed that RNF34 reduced TAK1 expression in a dose- and time-dependent manner. Ubiquitination assays confirmed that RNF34 can promote the ubiquitination of TAK1, and further experiments revealed that the proteasome inhibitor MG132 can block the degradation of TAK1. These findings indicate that RNF34 mediates the degradation of TAK1 through the ubiquitin-proteasome pathway, thereby acting as a negative regulator of innate immunity and inhibiting the NF-κB and IRF3 signaling pathways in miiuy croaker. This study identifies a crucial negative regulatory molecule in teleost fish.
