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.
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We are grateful to Dr. M. Bohgaki for providing the reagent for this study, Ms. M. Uchiumi for help in preparing the manuscript and Ms. M. Matsuo for technical assistance. We are also grateful to Dr. H. Hatakeyama, Dr. S. Kano, Dr. T. Mizumachi, Dr. T. Sakashita, Dr. K. Mizoguchi, Dr. A. Homma, and Dr. T. Suzuki for technical advice. This work was supported in part by KAKENHI (24112006, 24390065, 15H04690 to S.H.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by The Uehara Memorial Foundation and the Japan Rheumatism Foundation (to S.H.).
Conflict of interest
The authors declare no competing financial interests.
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Suzuki, M., Watanabe, M., Nakamaru, Y. et al. TRIM39 negatively regulates the NFκB-mediated signaling pathway through stabilization of Cactin. Cell. Mol. Life Sci. 73, 1085–1101 (2016). https://doi.org/10.1007/s00018-015-2040-x
- Ubiquitin ligase