Regulatory mechanism of the RNF168-SCCA1-MYH9 signaling axis in the response of ulcerative colitis

The potential function of E3 ubiquitin ligase RNF168 in inflammatory processes remains largely unexplored. Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by chronic inflammation and epithelial damage of the intestinal mucosa. The pathophysiology of UC is complex, and its mechanisms remain incompletely understood. This study explores the role of RNF168 in the pathogenesis of experimental colitis.

RNF168-knockout murine models were employed. The functional impact of RNF168 was determined by assessing colitis severity and susceptibility in these mice through a comprehensive evaluation of disease activity index, histological scoring, and pro-inflammatory cytokine levels. The molecular mechanism was explained using co-immunoprecipitation combined with mass spectrometry to identify and confirm downstream effectors.

We identified RNF168 as a susceptibility gene for colonic inflammation in mouse models and cell lines. RNF168 downregulation in colonic inflammation reduces SCCA1 ubiquitination, leading to SCCA1 accumulation. Increased SCCA1 contribute to inflammation by suppresses the MYH9-p53 signaling pathway, subsequently reduces the expression of p53 and phosphorylated p53 (p-p53), thereby exacerbating the inflammatory response. Administration of the small-molecule SCCA1 inhibitor 1-PPA alleviated colonic inflammation pathology. Our findings reveal a novel ubiquitination-dependent pathway and identify SCCA1 as a promising therapeutic target for colonic inflammation.

Our findings reveal a novel ubiquitination-dependent pathway in experimental colitis pathogenesis and identify SCCA1 as a promising therapeutic target for colitis. Elucidating these mechanisms opens avenues for developing therapies targeting inflammatory responses in UC.