Ubiquitin-specific protease 25 ameliorates ulcerative colitis by regulating the degradation of phosphor-STAT3

• Published in: Cell death & disease Vol. 16; no. 1; pp. 5 - 14
• Main Authors: Liu, Zhengru, Liu, Jian, Wei, Yuping, Li, Jinting, Zhang, Jixiang, Yu, Rong, Yang, Qian, Miao, Yinglei, Dong, Weiguo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.01.2025; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 13/21; 13/51; 14; 14/35; 38; 631/136/1425; 692/699/1503/257/1389; Animals; Antibodies; Biochemistry; Bioinformatics; Biomedical and Life Sciences; Cell Biology; Cell Culture; Colitis, Ulcerative - chemically induced; Colitis, Ulcerative - genetics; Colitis, Ulcerative - metabolism; Colitis, Ulcerative - pathology; Degradation; Dextran; Dextran Sulfate; Epithelial cells; Humans; Immunology; Immunoregulation; Inflammatory bowel disease; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestine; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Proteolysis; Stat3 protein; STAT3 Transcription Factor - metabolism; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; Ubiquitin-specific proteinase; Ubiquitination; Ulcerative colitis
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-07315-z

Ubiquitin-specific protease 25 (USP25), a member of the deubiquitination family, plays an important role in protein ubiquitination, degradation, inflammation, and immune regulation. However, the role and mechanism of USP25 in ulcerative colitis (UC) remain unclear. To study the role and mechanism of USP25 in UC, bioinformatics analysis and research are conducted on clinical patients with UC, Usp25 knockout ( Usp25 −/− ) mice, intestinal epithelial cell-specific knockout signal transducer and activator of transcription 3 ( Stat3) (Villin-Cre Stat3 fl/fl ) mice, and human colonic epithelial cells. Results show that the expression of USP25 is decreased in patients with UC and mice with dextran sulfate sodium salt (DSS)-induced colitis and that USP25 deficiency exacerbates UC by destroying the intestinal mucosal barrier, however, overexpression of USP25 can alleviate colitis. Mechanistically, USP25 reduces the degradation of phosphor-STAT3 Y705 at lysine 409 by catalyzing K48-linked deubiquitination. Further, this study demonstrates the aggravation of DSS-induced colitis by intestinal epithelial cell-specific knockout Stat3 in mice, while Stat3 overexpression by adeno-associated virus attenuates colitis in DSS-induced Usp25 −/− mice. Together, these results showed that USP25 ameliorates UC by regulating the degradation of phosphor-STAT3. Collectively, USP25 is a specific STAT3 regulator that can be targeted in UC.