title: TRAF4 acts as a silencer in TLR-mediated signaling through the association with TRAF6 and TRIF.
abstract: Toll-like receptors (TLR) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase play an essential role in intracellular eradication of engulfed pathogens. Here, we demonstrate the physical and functional association between components of the cytosolic NADPH oxidase and TLR-mediated signaling molecules. Cytosolic components of NADPH oxidase suppressed TLR-mediated NF-kappaB activation as well as IFN-beta promoter activation. We demonstrate that TNF-associated factor (TRAF) 4 associates with p47(phox), a component of cytosolic NADPH oxidase, and physically interacts and functionally counteracts with TRAF6 and Toll-IL-1 receptor (TIR) domain-containing adaptor-inducing IFN-beta (TRIF) molecules that critically regulate TLR-mediated signaling. TRAF4 mRNA expression was elicited in RPMI 8226 cells following LPS or CpG DNA treatment. These results suggest that TRAF4 participates in the molecular mechanism underlying silencing of TLR-mediated signaling through the interaction with molecules harboring phagosome/endosome membrane.
authors.affiliation: Department of Molecular Biodefense Research, Yokohama City University School of Medicine, Yokohama, Japan. takesita@yokohama-cu.ac.jp
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Takeshita
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.forename: Kouji
authors.initials: K
authors.lastname: Kobiyama
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Kojima
authors.forename: Cevayir
authors.initials: C
authors.lastname: Coban
authors.forename: Shin
authors.initials: S
authors.lastname: Sasaki
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ishii
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Klinman
authors.forename: Kenji
authors.initials: K
authors.lastname: Okuda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Koichi
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D002460:Cell Line; D003600:Cytosol / Q000201:enzymology; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000502:physiology*; D019255:NADPH Oxidases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D009838:Oligodeoxyribonucleotides / Q000378:metabolism; D010457:Peptidoglycan / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D053449:TNF Receptor-Associated Factor 4; D048029:TNF Receptor-Associated Factor 6 / Q000502:physiology*; D051193:Toll-Like Receptors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D020798:Two-Hybrid System Techniques
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D010457:Peptidoglycan; D010750:Phosphoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C470409:TICAM1 protein, human; D053449:TNF Receptor-Associated Factor 4; D048029:TNF Receptor-Associated Factor 6; C506367:TRAF4 protein, human; D051193:Toll-Like Receptors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases