controlled study, cytokine production, degradation, down regulation, embryo, gene, gene function, gene identification, gene interaction, gene overexpression, gene targeting, genetic association, human, human cell, lysosomal degradation, monocyte, promoter region, protein domain, protein function, protein protein interaction, proteomics, Tfg gene, TGF gene, TLR3 gene, transcription regulation, ubiquitination, virus detection
Health Research Board in Ireland, Science Foundation Ireland and National Institutes of Health.
In recent years members of the tripartite motif-containing (TRIM) family of E3 ubiquitin ligases have been shown to both positively and negatively regulate viral defence and as such are emerging as compelling targets for modulating the anti-viral immune response. In this study we identify TRIM68, a close homologue of TRIM21, as a novel regulator of Toll-like receptor (TLR)- and RIG-I-like receptor (RLR)-driven type I IFN production. Proteomic analysis of TRIM68-containing complexes identified TRK-fused gene (TFG) as a potential TRIM68 target. Overexpression of TRIM68 and TFG confirmed their ability to associate, with TLR3 stimulation appearing to enhance the interaction. TFG is a known activator of NF-κB via its ability to interact with inhibitor of NF-κB kinase subunit gamma (IKK-γ) and TRAF family member-associated NF-κB activator (TANK). Our data identifies a novel role for TFG as a positive regulator of type I IFN production and suggests that TRIM68 targets TFG for lysosomal degradation, thus turning off TFG-mediated IFN-β production. Knockdown of TRIM68 in primary human monocytes resulted in enhanced levels of type I IFN and TFG following poly(I:C) treatment. Thus TRIM68 targets TFG, a novel regulator of IFN production, and in doing so turns off and limits type I IFN production in response to anti-viral detection systems.
Wynne C, Lazzari E, Smith S, McCarthy EM, Ní Gabhann J, Kallal LE, Higgs R, Cryan SA, Biron CA, Jefferies CA. TRIM68 negatively regulates IFN-β production by degrading TRK fused gene, a novel driver of IFN-β downstream of anti-viral detection systems. PLoS One. 2014;9(7):e101503.