Epithelial TRIM27 Inhibits Intestinal Inflammation in Ulcerative Colitis by the USP7/TRIM27-IKK Double Negative-Feedback

Abstract

The E3 ubiquitin ligase tripartite motif 27 (TRIM27) is a negative regulator of NF-κB activation and the innate immune response, and TRIM27 deficiency significantly impairs dextran sulfate sodium (DSS)-induced colitis. The function of TRIM27 in intestinal epithelial cells (IECs), the mechanism by which TRIM27 inhibits the NF-κB pathway and its dysregulation in ulcerative colitis (UC) remain unclear. Here, it is report that epithelial TRIM27 functions as an anti-inflammatory factor that inhibited intestinal inflammation in IECs in vitro and in epithelial Trim27 knockout mice in vivo. Mechanistically, TRIM27 destabilized IKKα and TRAF6 via polyubiquitination of IKKα at the K569 site and TRAF6 at the K489 site. In response to TNF-α, IKKβ phosphorylated TRIM27 at S173 to decrease TRIM27 expression by impairing its binding to ubiquitin-specific protease 7 (USP7) and USP7-mediated TRIM27 deubiquitination. Notably, overexpression of TRIM27 enhanced the anti-inflammatory effect of infliximab (IFX) in IECs. TRIM27 is downregulated in inflamed colons from UC patients and is associated with the therapeutic effect of IFX. Overall, this study identifies epithelial TRIM27 as a bona fide negative modulator of intestinal inflammation and USP7/TRIM27-IKK as a new double negative feedback mechanism of the NF-κB pathway, which supports the use of TRIM27 replenishment as a potential therapeutic strategy for UC.