TRIM68 Negatively Regulates IFN-β Production by Degrading TRK Fused Gene, a Novel Driver of IFN-β Downstream of Anti-Viral Detection Systems

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.

RETRACTED ARTICLE: Clostridium difficile toxin B induces colonic inflammation through the TRIM46/DUSP1/MAPKs and NF-κB signalling pathway

“…As expected, treatment of FHC cells with TcdB at concentrations ranging from 100 to 400 significantly induced DUSP1 ubiquitination in a dose-dependent manner (Figure 2(D)). Meanwhile, TRIM family proteins that act as E3-ubiquitin ligases, including TRIM8, TRIM11, TRIM22, TRIM24, TRIM46, TRIM52, TRIM65 and TRIM68, have been found to be associated with inflammatory response [20][21][22][29][30][31][32][33] and are therefore examined in response to TcdB. As shown in Figure 2(E), FHC cells with 200 ng/ml TcdB treatment for 24 h markedly decreased the mRNA expression of TRIM22 by 18.6% and increased the mRNA expression of TRIM8, TRIM11, TRIM24, TRIM46, TRIM52 and TRIM65 by 20.8%, 48.7%, 24.6%, 200.9%, 50.1% and 103.8%, respectively, compared with control.…”

Insights into the Antiviral Immunity against Grass Carp (Ctenopharyngodon idella) Reovirus (GCRV) in Grass Carp

“…Recently, studies highlight the positive or negative roles of TRIM in innate immune response preventing or curtailing pathogen invasion [ 170 , 173 ]. Multiple TRIM members involve in antiviral immunity at various levels of the IFN signaling cascade [ 170 , 174 ]: some TRIMs are IFN inducible and restrict viral infection such as TRIM5, TRIM8, and TRIM22 [ 175 – 177 ], while some TRIMs expressions mediate the production of IFN such as TRIM25, TRIM21, and TRIM68 [ 174 , 178 – 180 ]. This is why researchers classify TRIMs into ISG families [ 7 , 142 ].…”

Bathyal and abyssal demersal bait-attending fauna of the Eastern Mediterranean Sea

“…Luring animals with bait to a camera helps to amplify the low density of deep-sea mobile faunal and is particularly adept at recording large mobile carnivores that are often able to avoid other survey methods (Bailey et al 2007 ; Harvey et al 2007 ). The method emulates a natural process, the arrival of a carcass at the seabed, which is distinct from the input of particulate material from the surface (Mahaut et al 1990 ; Drazen et al 2008 ; Higgs et al 2014 ). The method is highly selective, however, and the proportion of the mobile fauna that respond to bait varies with location and depth (Priede and Merrett 1996 ; Yau et al 2001 ) and is likely related to how regularly that location experiences a natural food fall (Cartes et al 2016 ).…”

“…Necrophagivores are attracted to bait to exploit the higher density of prey species, often amphipods, in the vicinity (Bozzano and Sardaà 2002 ; Castro et al 2005 ; Kemp et al 2006 ; Stoner et al 2008 ; Linley et al 2016 , 2017a ; Drazen and Sutton 2017 ), although they may use bait odour to locate the prey. Other species such as the blackbelly rosefish and some Zoarcid species may use the associated structures as a habitat as well as hunting grounds (Higgs et al 2014 ; Jamieson et al 2017 ; Linley et al 2017b ). For these reasons, the fauna observed by baited camera deployed using the lander methods are henceforth described as ‘bait-attending’.…”