The Function of TRIM25 in Antiviral Defense and Viral Immune Evasion

Figures

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  Figure 1. Illustration of TRIM25 monomer and dimer structures and possible RING dimerization modes. (A) The structure of TRIM25, possessing a RING domain, a B-box domain, a coiled-coil domain, and a SPRY/PRY domain. (B) The structure of a TRIM25 dimer. (C) The possible modes of RING dimerization. This dimerization stabilizes the closed conformation, activates thioester intermediates, and facilitates ubiquitin transfer in chain synthesis. (Ca) The RING domains of two TRIM25 dimers interact to form a TRIM25 tetramer. (Cb) TRIM25 dimers link laterally in an end-to-end configuration for the formation of TRIM25 tetramer. (Cc) B-box domain contributes to RING dimerization by binding to the CC domain, which shortened the distance between two RING domains within a TRIM25 dimer. (This figure was created using BioRender. Liu, Q.X. https://BioRender.com/r07m967, accessed on 7 March 2025).

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  Figure 2. Biological functions of TRIM25 in SARS-CoV-2 infection and cancer cell survival. (A) SARS-CoV-2 proteins participate in viral immune evasion by interfering with antiviral signaling. SARS-CoV-2 viral RNA can activate TRIM25 and RIG-I for the subsequent aggregation of MAVS, which regulate IRF3/7 and IFN production. The IFNs produced bind to a type I IFN receptor to activate the JAK/STAT signaling pathway, leading to the production of ISGs. Both the SARS-CoV-2 nucleocapsid protein (NP) and ORF6 proteins influence the nuclear translocation of IRF3/7 and STAT. The NP recruits G3BP2 and TRIM25, while ORF6 mediates TRIM25 degradation, limiting TRIM25-mediated RIG-I ubiquitination. (B) TRIM25-mediated ubiquitination regulates multiple biological pathways. (Ba) TRIM25 can lead to the degradation of Keap1, resulting in the nuclear translocation of Nrf2 and the production of antioxidant proteins. (Bb) 14-3-3σ can be degraded by TRIM25-mediated ubiquitination, which contributes to the degradation of Mdm2 and p53. (Bc) The inhibitory effect of GPX4 on ferroptosis is negated by the participation of TRIM25 in the treatment of N6F11. (Bd) Neddylated TRIM25 can induce the nuclear translocation of…

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  Figure 3. TRIM25 regulates the RIG-I- and MDA5-mediated antiviral and TRAF2/TNFα signaling pathways. RIG-I/MDA5 remains in a closed conformation until the binding of viral RNA to open the RIG-I CARDs domain. TRIM25 ubiquitinates RIG-I to trigger RIG-I/IFN signaling. TRIM25 also binds to 14-3-3ε to enable RIG-I activation and accumulation and interacts with TRAF6 to induce downstream signaling. In addition, TRIM25 can modify TRAF2, a member of the TRAF family, independently of RIG-I/MDA5 signaling. (This figure was created using BioRender. Liu, Q.X. https://BioRender.com/h64h569, accessed on 17 March 2025).