USP43 Inhibits Intestinal Inflammation via TRAF4-mediated NF-κB Signaling.

Ulcerative colitis (UC) is a chronic inflammatory intestinal disorder; however, its exact pathophysiological mechanisms remain elusive. Through integrated RNA-seq and proteome analyses, we revealed that ubiquitin-specific protease 43 (USP43) expression is significantly decreased in dextran sulfate sodium (DSS)-induced colitis. USP43 expression was also lower in UC patients than that in healthy controls. Furthermore, USP43 deficiency in mice exacerbated DSS-induced colitis. In lipopolysaccharide (LPS)-treated RAW264.7 cells, USP43 overexpression inhibited, whereas USP43 knockdown promoted the phosphorylation of p65 and the production of proinflammatory cytokines; NF-κB-specific inhibitor JSH-23 reversed the facilitatory effect of USP43 knockdown on inflammatory cytokines. Mechanistically, USP43 interacts with and deubiquitinates TRAF4, thereby inhibiting NF-κB signaling and reducing proinflammatory cytokine levels. Importantly, TRAF4 overexpression partially reversed the increase in LPS-mediated NF-κB activation caused by USP43 knockdown. Collectively, our findings highlight a novel role for USP43 in suppressing intestinal inflammation through the inhibition of TRAF4-mediated NF-κB activation. These results reveal a new mechanism involving the USP43/TRAF4 axis in the regulation of intestinal inflammation.