Suzuki Masanobu, Watanabe Masashi, Nakamaru Yuji, Takagi Dai, Takahashi Hidehisa, Fukuda Satoshi, Hatakeyama Shigetsugu
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.
Cell Mol Life Sci. 2016 Mar;73(5):1085-101. doi: 10.1007/s00018-015-2040-x. Epub 2015 Sep 12.
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.
核因子κB（NFκB）是细胞存活、免疫、炎症、致癌作用和器官发生的核心调节因子之一。NFκB的激活受到包括磷酸化、NEDD化和泛素化在内的多种翻译后修饰的严格调控。几种类型的泛素化在NFκB信号通路的多步骤调节中发挥重要作用。一些作为E3泛素连接酶发挥作用的含三联体基序（TRIM）蛋白已知可调节各种生物学过程，如炎症信号通路。TRIM家族蛋白之一的TRIM39，其基因存在单核苷酸多态性，已被确定为白塞病的遗传因素之一。然而，TRIM39在炎症信号传导中的作用尚未完全阐明。在本研究中，为了阐明TRIM39在炎症信号传导中的功能，我们以TRIM39为诱饵进行酵母双杂交筛选，并鉴定出Cactin，据报道它可抑制NFκB和TLR介导的转录。我们发现TRIM39可稳定Cactin蛋白，并且在肿瘤坏死因子α（TNFα）刺激后Cactin会上调。敲低TRIM39也会导致NFκB信号的激活。这些发现表明，TRIM39与TNFα等炎症刺激物诱导的Cactin协同作用，对NFκB信号起负调节作用。
