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TRIM25 and its emerging RNA‐binding roles in antiviral defense

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Abstract The innate immune system is the body's first line of defense against viruses, with pattern recognition receptors (PRRs) recognizing molecules unique to viruses and triggering the expression of interferons and other anti‐viral cytokines, leading to the formation of an anti‐viral state. The tripartite motif containing 25 (TRIM25) is an E3 ubiquitin ligase thought to be a key component in the activation of signaling by the PRR retinoic acid‐inducible gene I protein (RIG‐I). TRIM25 has recently been identified as an RNA‐binding protein, raising the question of whether its RNA‐binding activity is important for its role in innate immunity. Here, we review TRIM25's mechanisms and pathways in noninfected and infected cells. We also introduce models that explain how TRIM25 binding to RNA could modulate its functions and play part in the antiviral response. These findings have opened new lines of investigations into functional and molecular roles of TRIM25 and other E3 ubiquitin ligases in cell biology and control of pathogenic infections. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition
Possible models of dimerization of the RING domains of TRIM25 dimers as proposed by Sanchez et al. Due to the anti‐parallel structure of the TRIM25 dimer, RING domains from TRIM25 molecules found in the same dimer cannot dimerize themselves. This implies that higher order oligomerization is required for TRIM25's catalytic activity
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Model of TRIM25 binding to RNA. The major point of contact between RNA and TRIM25 is the PRY/SPRY domain. Additional RNA‐binding activity has been attributed to a 7 Lysine peptide (7K) and the Coiled‐coil domain. TRIM25 has been shown to bind both single and double‐stranded RNAs
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RNA‐binding is necessary for TRIM25's E3 ligase ubiquitin activity and activation of its partner—RNA‐binding protein zinc‐finger antiviral protein
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Model of activation of RIG‐I based on the sequential ubiquitination model proposed by Okamoto et al. Upon recognition of 5′ppp‐dsRNA, RIG‐I undergoes a conformational change and the Helicase‐CTD linker can be ubiquitinated by Riplet. This releases the 2CARDs from auto‐repression and allows their dephosphorylation by PP1. Ubiquitination of the linker also promotes the assembly of other RIG‐I molecules along the dsRNA, although the CTD of only one molecule can bind the 5′ppp moiety. The 2CARDs from RIG‐I molecules assembled along the dsRNA can form “tetramer” structures that are stabilized by K63‐linked polyubiquitination of the 2CARD. This ubiquitination is performed by several E3 ubiquitin ligases including TRIM25, MEX3C, TRIM4, and Riplet. This tetramer structure interacts with the CARDs of MAVS and promotes its oligomerization, leading to further downstream signaling and expression of type I interferon
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA in Disease and Development > RNA in Disease

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