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

Claire Wynne,Joan Ní Gabhann,Christine A Biron,Rowan Higgs,Caroline A Jefferies,Sally Ann Cryan,Eoghan M Mccarthy,Siobhán Smith,Elisa Lazzari,Lara E Kallal

doi:10.1371/journal.pone.0101503

Abstract

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.

Highlights

Innate immune receptors play key roles in viral recognition and activation of transcription factors important for driving both type I IFN and pro-inflammatory cytokine production
TRIM68 is a novel negative regulator of Toll-like receptor (TLR)/RIG-I-like receptor (RLR)-driven IFN-b promoter activity. Both TRIM21 and TRIM68 have previously been identified as targets for autoantibody production in systemic lupus erythematosus (SLE) [34,35]
Like TRIM21 and the other proteins found in this cluster, TRIM68 contains a SPRY/PRY domain, a domain which has been shown to be important in immune regulation

Summary

Introduction

Innate immune receptors play key roles in viral recognition and activation of transcription factors important for driving both type I IFN and pro-inflammatory cytokine production. RIG-I and melanoma differentiationassociated protein 5 (MDA-5) have been shown to recognise viral RNA whereas multiple DNA-receptors exist (reviewed in [14,15]) Once activated these PRRs recruit adaptor proteins, such as TIR domain-containing adaptor protein inducing interferon-b (TRIF) and myeloid differentiation primary response gene 88 (MyD88) to the TLRs and mitochondrial anti-viral signalling protein (MAVS) to the RLRs, which facilitate the formation of signalling complexes that result in the activation of downstream kinases such as IkB kinases and TANK-binding kinase 1 (TBK1). Together these regulate the activity of the transcription factors NF-kB and the IRF family members (IRF3 and 7) and the subsequent production of pro-inflammatory cytokines and type I IFNs (reviewed in [16])

Methods

Results

Conclusion