TRIM68 negatively regulates IFN-β production by degrading TRK fused gene, a novel driver of IFN-β downstream of anti-viral detection systems

• Published in: PloS one 2014-07, Vol.9 (7), p.e101503-e101503
• Main Authors: Wynne, Claire, Lazzari, Elisa, Smith, Siobhán, McCarthy, Eoghan M, Ní Gabhann, Joan, Kallal, Lara E, Higgs, Rowan, Greco, Angela, Cryan, Sally Ann, Biron, Christine A, Jefferies, Caroline A
• Format: Article
• Language: English
• Subjects: Antiviral agents; Autoantigens - chemistry; Autoantigens - metabolism; Bacterial infections; Biology and Life Sciences; Cytokines; DEAD Box Protein 58; DEAD-box RNA Helicases - metabolism; Deoxyribonucleic acid; DNA; Enzyme inhibitors; Garra; Genes; HEK293 Cells; HeLa Cells; Homology; Humans; IKK protein; Immune response; Immune system; Immunity, Innate; Immunology; Interferon-beta - biosynthesis; Interferon-beta - genetics; Kinases; Lysosomes; Melanoma; Monocytes; NF-κB protein; Polyinosinic:polycytidylic acid; Promoter Regions, Genetic - genetics; Prostate cancer; Protein Structure, Tertiary; Proteins; Proteins - metabolism; Proteolysis; Receptors, Immunologic; TLR3 protein; Toll-like receptors; Transcription factors; Tripartite Motif Proteins; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Viruses - immunology; β-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0101503

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.