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 (SNPs), 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.

Enhancement of Th1/Th17 inflammation by TRIM21 in Behçet’s disease

“…The evidence supports a new pathogenic model in which the modulation of ubiquitination is responsible for the distinct immune reaction in BD 19 . TRIM proteins activate innate immune signaling pathways, including NF-kB, AP-1, and IRFs, by generating ubiquitin signals 20 .…”

“…A recent genetic study on BD revealed that TRIM39 is associated with a genetic predisposition to this disease 21 . TRIM39 regulates the NF-κB signal negatively by modulating the production of inflammatory cytokines, such as TNF-α 19 . From the classical view on the immunologic abnormalities in BD patients, strong Th1 immune response occurs in active BD 22 .…”

Human cactin interacts with DHX8 and SRRM2 to assure efficient pre-mRNA splicing and sister chromatid cohesion

“…Overexpression of Cactin in a Cactus-compromised background enhanced cactus phenotypes including embryonic lethality and embryo ventralization (Lin et al, 2000). Human cactin was later found to physically and functionally interact with IκB-like protein (IκBL) and to be part of a negative feedback loop that controls NFκB transcriptional response (Suzuki et al, 2016), suggesting a conserved function for cactins in immune response and development (Atzei et al, 2010a). To date, cactin orthologs have been studied also in Toxoplasma gondii, Litopenaeus vannamei, Arabidopsis thaliana, Caenorhabditis elegans, and Danio rerio (Atzei et al, 2010b;Baldwin et al, 2013;Cecchetelli et al, 2016;Doherty et al, 2014;LaBonty et al, 2014;Szatanek et al, 2012;Tannoury et al, 2010;Zhang et al, 2014).…”

The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3

“…Several TRIM family members (including TRIM31, TRIM40, TRIM10, TRIM15, TRIM26 and TRIM39) are organized in a tight cluster and two TRIM genes (including TRIM38 and TRIM27) telomeric of the cluster within the MHC class I region20. Most of the above mentioned TRIM family members possess vital regulatory effects in innate immune responses1921222324252627. However, the biological function of TRIM31, especially in the innate immune response, remains unknown.…”