title: TRIM39 negatively regulates the NFκB-mediated signaling pathway through stabilization of Cactin.
abstract: NFκB is one of the central regulators of cell survival, immunity, inflammation, carcinogenesis and organogenesis. The activation of NFκB is strictly regulated by several posttranslational modifications including phosphorylation, neddylation and ubiquitination. Several types of ubiquitination play important roles in multi-step regulations of the NFκB pathway. Some of the tripartite motif-containing (TRIM) proteins functioning as E3 ubiquitin ligases are known to regulate various biological processes such as inflammatory signaling pathways. One of the TRIM family proteins, TRIM39, for which the gene has single nucleotide polymorphisms, has been identified as one of the genetic factors in Behcet's disease. However, the role of TRIM39 in inflammatory signaling had not been fully elucidated. In this study, to elucidate the function of TRIM39 in inflammatory signaling, we performed yeast two-hybrid screening using TRIM39 as a bait and identified Cactin, which has been reported to inhibit NFκB- and TLR-mediated transcriptions. We show that TRIM39 stabilizes Cactin protein and that Cactin is upregulated after TNFα stimulation. TRIM39 knockdown also causes activation of the NFκB signal. These findings suggest that TRIM39 negatively regulates the NFκB signal in collaboration with Cactin induced by inflammatory stimulants such as TNFα.
authors.affiliation: Department of Biochemistry, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.|Department of Otolaryngology-Head and Neck Surgery, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Biochemistry, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamaru
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Takagi
authors.affiliation: Department of Biochemistry, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukuda
authors.affiliation: Department of Biochemistry, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. hatas@med.hokudai.ac.jp.
authors.forename: Shigetsugu
authors.initials: S
authors.lastname: Hatakeyama
mesh_terms: D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D029721:Drosophila Proteins / Q000032:analysis / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism*; D011485:Protein Binding; D060066:Protein Interaction Maps; D055550:Protein Stability; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; D029721:Drosophila Proteins; D016328:NF-kappa B; C414093:cactin protein, Drosophila; C414583:TRIM39 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: E3; IκBα; RelA/p65; TLR; Ubiquitin; Ubiquitin ligase