title: 14-3-3-zeta participates in TLR3-mediated TICAM-1 signal-platform formation.
abstract: Recognition of pathogen-associated molecular patterns (PAMPs) by pattern-recognition receptors (PRRs) is important in innate immune signaling. Toll-like receptors (TLRs) are well-characterized PRRs and are pivotal in antiviral and antitumor host defense. TIR domain-containing adaptor molecule 1 (TICAM-1, also called TRIF) is an adapter molecule in TLR3- and TLR4-mediated IRF3 activation, late-phase NF-κB activation and MAPK-mediated AP-1 activation. When a TLR3 ligand is added to TLR3-positive cells, TICAM-1 transiently interacts with TLR3 and forms multimers in the cytosol. However, the precise mechanism of TICAM-1 multimer formation remains unknown. In this study, we identified 14-3-3-zeta as a molecule that functions in TLR3-mediated signaling. Knockdown of 14-3-3-zeta reduced production of type I interferon and inflammatory cytokines, nuclear translocation of IRF3 and phosphorylation of IκB via the TLR3-TICAM-1 pathway. Furthermore, TICAM-1 multimerization by ligand stimulation was prohibited by 14-3-3-zeta knockdown. These results suggest that 14-3-3-zeta is involved in the TLR3-TICAM-1 pathway in promoting multimerization of TICAM-1 for the formation of a TICAM-1 signalosome.
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Funami
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Division of Molecular Life Science, Graduate School of Life Science, Hokkaido University, Sapporo 001-0021, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Obuse
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan. Electronic address: seya-tu@pop.med.hokudai.ac.jp.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
mesh_terms: D048948:14-3-3 Proteins / Q000276:immunology*; D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000276:immunology*
chemical_list: D048948:14-3-3 Proteins; D033942:Adaptor Proteins, Vesicular Transport; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; C572235:YWHAZ protein, human
keywords: NF-κB; Poly I:C; Signalosome; TICAM-1 (TRIF); TLR3; Type I interferon