title: TRIM59 interacts with ECSIT and negatively regulates NF-κB and IRF-3/7-mediated signal pathways.
abstract: Innate immune responses are triggered by pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs) and then activate intracellular signaling pathways including NF-κB and interferon regulatory factors. Recently, it has been reported that tripartite motif (TRIM) proteins function as crucial regulators via ubiquitin-mediated modifications for these signaling pathways. In this study, we showed that one of the TRIM family ubiquitin ligases, TRIM59, interacts with ECSIT as an adaptor protein required for the TLR-mediated transduction pathway. Luciferase reporter assays using reporter plasmids including NF-κB responsive element, interferon β (IFN-β) promoter and interferon-sensitive response element (ISRE) showed that overexpression of TRIM59 repressed their transcriptional activities, whereas knockdown of TRIM59 enhanced their transcriptional activities. Furthermore, TRIM59 inhibited phosphorylation and dimerization of IRF3 and IRF7, suggesting that TRIM59 negatively regulates upstream kinases for IRFs. These findings indicate that TRIM59 may serve as a multifunctional regulator for innate immune signaling pathways.
authors.affiliation: Department of Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kondo
authors.forename: Masashi
authors.initials: M
authors.lastname: Watanabe
authors.forename: Shigetsugu
authors.initials: S
authors.lastname: Hatakeyama
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008667:Metalloproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D055503:Protein Multimerization; D015398:Signal Transduction; D000070584:Tripartite Motif Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C518657:Ecsit protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008667:Metalloproteins; D016328:NF-kappa B; C530864:TRIM59 protein, human; C464783:Trim59 protein, mouse; D000070584:Tripartite Motif Proteins