title: TGF-β1 inhibits the production of IFN in response to CpG DNA via ubiquitination of TNF receptor-associated factor (TRAF) 6.
abstract: The effect of TGF-β1 on CpG DNA-induced type I IFN production was examined by reconstituting a series of signaling molecules in TLR 3 signaling. TGF-β1 inhibited CpG DNA-induced IFN-α4 productivity in HeLa cells. Transfection of IFN regulatory factor (IRF)7 but not TNF receptor-associated factor (TRAF)6 and TRAF3 into cells triggered IFN-α4 productivity, and TGF-β1 inhibited IRF7-mediated type I IFN production in the presence of TRAF6. TGF-β1 induced ubiquitination of TRAF6, although CpG DNA did not induce it. Moreover, TGF-β1 accelerated the ubiquitination of TRAF6 in the presence of CpG DNA. TGF-β1 ubiquitinated TRAF6 at K63 but not K48. TGF-β1 also induced ubiquitination of IRF7. Further, TGF-β1 did not impair the interaction of IRF7 and TRAF6. CpG DNA induced the phosphorylation of IRF7 in the presence of TRAF6, whereas TGF-β1 inhibited the IRF7 phosphorylation. Blocking of TRAF6 ubiquitination abolished the inhibition of CpG DNA-induced type I IFN production by TGF-β. Taken together, TGF-β was suggested to inhibit CpG DNA-induced type I IFN production transcriptionally via ubiquitination of TRAF6.
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan naikiy@aichi-med-u.ac.jp.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Naiki
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Komatsu
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Koide
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan Division of Pediatrics Infectious Disease and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Jargalsaikhan
authors.initials: J
authors.lastname: Dagvadorj
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Division of Pediatrics Infectious Disease and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Moshe
authors.initials: M
authors.lastname: Arditi
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokochi
mesh_terms: D004247:DNA / Q000235:genetics; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C408982:CPG-oligonucleotide; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D053773:Transforming Growth Factor beta1; D004247:DNA
keywords: CpG DNA; Transforming growth factor-β1; tumor necrosis factor receptor-associated factor 6; type I interferon; ubiquitination