Dishevelled interacts with p65 and acts as a repressor of NF-κB-mediated transcription

Abstract

Dishevelled (Dvl) is a highly conserved protein family that plays an important role in mediating Wnt signaling from membrane to cytoplasm. Recently we reported that Dvl also functions in the nucleus by stabilizing the β-catenin/TCFs transcriptional complex. Here we describe that Dvl may function as a repressor of NF-κB. Our data show that Dvl directly binds to p65 and their interaction occurs in the nucleus. Dvl expression inhibits p65-mediated or TNF-α-stimulated activation of the NF-κB dependent reporter. This action of Dvl, however, is not dependent on Wnt or its downstream effector β-catenin. Chromatin immunoprecipitation assay shows that recruitment of p65 to the promoters of NF-κB target genes is significantly enhanced when expression of Dvl is knocked down. Consistently, the expression level of a subset of NF-κB target genes is also increased after knock-down of Dvl. Moreover, our data suggest that Dvl may relieve the anti-apoptotic effect of NF-κB, thus play a role in promoting apoptosis. Therefore, this work demonstrates a novel function of Dvl in modulating NF-κB-regulated gene transcription.

Dishevelled2 promotes apoptosis and inhibits inflammatory cytokine secretion in rheumatoid arthritis fibroblast-like synoviocytes through crosstalk with the NF-κB pathway

“…The results showed that overexpression of Dvl2 inhibited TNF-α-induced nuclear translocation of P65 (Figure 6A). Deng N et al reported that Dvl can interact with P65 in HEK293T cells [26], and our immunoprecipitation (IP) analysis also showed interaction between Dvl2 and P65 in RA-FLSs (Figure 6B). A subsequent chromosome immunoprecipitation (ChIP) assay revealed that Dvl2 inhibited TNF-α-induced binding of P65 to the promoters of anti-apoptotic and inflammatory genes (Figure 6C, 6D).…”

The E3 Ubiquitin Ligase ITCH Negatively Regulates Canonical Wnt Signaling by Targeting Dishevelled Protein

“…On the other hand, recent findings indicated that Dvl also exists in the nucleus (9,14,41) and participates in ␤-catenin-T-cell factor (TCF) transcriptional complex formation by interacting with ␤-catenin and c-Jun, thus promoting canonical Wnt signaling (9). In addition, Dvl was also reported to interact with p65 in the nucleus to inhibit p65-mediated transcription (8).…”

Dishevelled‐3 activates p65 to upregulate p120‐catenin transcription via a p38‐dependent pathway in non‐small cell lung cancer

“…Free p65 subsequently translocates into the nucleus where it functions as a transcription factor in regulating its target genes . Prior study had suggested that Dvl interacted with p65 in the nucleus and inhibited NF‐κB‐mediated transcription . In this study, we have demonstrated that Dvl‐3 transfection promoted phosphorylation of IκB‐α and facilitated nuclear translocation of p65, suggesting p65 may be activated by Dvl‐3 induced phosphorylation of IκB‐α.…”