The Function And Mechanism Of E3 Ubiquitin Ligase TRIM21 In Colitis And Colon Cancer

Colitis is a common intestinal disease accompanied by intestinal epithelial damage and inflammation,which is caused by a variety of factors.The proliferation of intestinal epithelial cells after colitis is important for intestinal epithelium repair.Long-term chronic colitis has a large probability to develop colon cancer,and the malignant proliferation of intestinal epithelial cells initiates this process.TRIM21 is a well-known E3 ubiquitin ligase,which was originally found in systemic lupus erythematosus,and participated in the pathogenesis of systemic lupus erythematosus.Increasing clinical studies have shown that systemic lupus erythematosus and colitis are closely related.However,the role of TRIM21 in colitis remains unknown.In this study we found that TRIM21 was up-regulated in DSS-induced colitis and demonstrated that the deficiency of TRIM21 in mice enhanced the resistance to colitis,and TRIM21-deficient mice were less likely to lose weight and increased the survival rate.We further confirmed that TRIM21 in intestinal epithelial cells was involved in colitis by bone marrow transfer experiments.Mechanistically,TRIM21 bound to β-catenin and regulated the stability of P-catenin via K48-linked ubiquitination.Compared with WT mice,the expression of P-catenin in intestinal epithelial cells was significantly increased in TRIM21-deficient mice.Consistent with increased β-catenin,the expression of CyclinD1,one of P-catenin target genes,was also up-regulated and the proliferation of intestinal epithelial cells was significantly increased.In addition,we found the expression of TRIM21 was reduced in human colon cancer.Compared with WT mice,the occurrence of colon cancer was increased in TRIM21-deficient mice treated with AOM/DSS.Moreover,we found that IFN-y induced TRIM21 expression in intestinal epithelial cells.IFN-y was up-regulated in colitis and down-regulated in colon cancer,thus leading to high expression of TRIM21 in colitis but low expression in colon cancer.Taken together,we found that TRIM21 can modulate the stability ofβ-catenin via ubiquitination and revealed the role of TRIM21 in the pathogenesis of colitis and colon cancer.These finding provide new insights into the pathogenesis of colitis and colon cancer and provide a potential target for drug development for colitis and colon cancer.