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

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...

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Autores principales: Wynne, Claire, Lazzari, Elisa, Smith, Siobhán, McCarthy, Eoghan M., Ní Gabhann, Joan, Kallal, Lara E., Higgs, Rowan, Cryan, Sally Ann, Biron, Christine A., Jefferies, Caroline A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4084880/
https://www.ncbi.nlm.nih.gov/pubmed/24999993
http://dx.doi.org/10.1371/journal.pone.0101503
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author Wynne, Claire
Lazzari, Elisa
Smith, Siobhán
McCarthy, Eoghan M.
Ní Gabhann, Joan
Kallal, Lara E.
Higgs, Rowan
Cryan, Sally Ann
Biron, Christine A.
Jefferies, Caroline A.
author_facet Wynne, Claire
Lazzari, Elisa
Smith, Siobhán
McCarthy, Eoghan M.
Ní Gabhann, Joan
Kallal, Lara E.
Higgs, Rowan
Cryan, Sally Ann
Biron, Christine A.
Jefferies, Caroline A.
author_sort Wynne, Claire
collection PubMed
description 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.
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spelling pubmed-40848802014-07-09 TRIM68 Negatively Regulates IFN-β Production by Degrading TRK Fused Gene, a Novel Driver of IFN-β Downstream of Anti-Viral Detection Systems Wynne, Claire Lazzari, Elisa Smith, Siobhán McCarthy, Eoghan M. Ní Gabhann, Joan Kallal, Lara E. Higgs, Rowan Cryan, Sally Ann Biron, Christine A. Jefferies, Caroline A. PLoS One Research Article 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. Public Library of Science 2014-07-07 /pmc/articles/PMC4084880/ /pubmed/24999993 http://dx.doi.org/10.1371/journal.pone.0101503 Text en © 2014 Wynne et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Wynne, Claire
Lazzari, Elisa
Smith, Siobhán
McCarthy, Eoghan M.
Ní Gabhann, Joan
Kallal, Lara E.
Higgs, Rowan
Cryan, Sally Ann
Biron, Christine A.
Jefferies, Caroline A.
TRIM68 Negatively Regulates IFN-β Production by Degrading TRK Fused Gene, a Novel Driver of IFN-β Downstream of Anti-Viral Detection Systems
title TRIM68 Negatively Regulates IFN-β Production by Degrading TRK Fused Gene, a Novel Driver of IFN-β Downstream of Anti-Viral Detection Systems
title_full TRIM68 Negatively Regulates IFN-β Production by Degrading TRK Fused Gene, a Novel Driver of IFN-β Downstream of Anti-Viral Detection Systems
title_fullStr TRIM68 Negatively Regulates IFN-β Production by Degrading TRK Fused Gene, a Novel Driver of IFN-β Downstream of Anti-Viral Detection Systems
title_full_unstemmed TRIM68 Negatively Regulates IFN-β Production by Degrading TRK Fused Gene, a Novel Driver of IFN-β Downstream of Anti-Viral Detection Systems
title_short TRIM68 Negatively Regulates IFN-β Production by Degrading TRK Fused Gene, a Novel Driver of IFN-β Downstream of Anti-Viral Detection Systems
title_sort trim68 negatively regulates ifn-β production by degrading trk fused gene, a novel driver of ifn-β downstream of anti-viral detection systems
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4084880/
https://www.ncbi.nlm.nih.gov/pubmed/24999993
http://dx.doi.org/10.1371/journal.pone.0101503
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