title: 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.
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland; School of Biological Sciences, Dublin Institute of Technology, Dublin, Ireland.
authors.forename: Claire
authors.initials: C
authors.lastname: Wynne
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lazzari
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Siobhán
authors.initials: S
authors.lastname: Smith
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Eoghan M
authors.initials: EM
authors.lastname: McCarthy
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Joan
authors.initials: J
authors.lastname: Ní Gabhann
authors.affiliation: Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Lara E
authors.initials: LE
authors.lastname: Kallal
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Rowan
authors.initials: R
authors.lastname: Higgs
authors.forename: Angela
authors.initials: A
authors.lastname: Greco
authors.affiliation: School of Pharmacy, Royal College of Surgeons in Ireland, Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin, Dublin, Ireland.
authors.forename: Sally Ann
authors.initials: SA
authors.lastname: Cryan
authors.affiliation: Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Biron
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Jefferies
mesh_terms: D001324:Autoantigens / Q000737:chemistry / Q000378:metabolism*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D059748:Proteolysis; D011971:Receptors, Immunologic; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D054875:Ubiquitination; D014780:Viruses / Q000276:immunology*; D033921:Vesicular Transport Proteins
chemical_list: D001324:Autoantigens; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D016899:Interferon-beta; D011506:Proteins; D011971:Receptors, Immunologic; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; C096163:TFG protein, human; D033921:Vesicular Transport Proteins; C437970:TRIM68 protein, human; C452820:RIGI protein, human