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Lipopolysaccharide-regulated RNF31/NRF2 axis in colonic epithelial cells mediates homeostasis of the intestinal barrier in ulcerative colitis

  • 0Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China; Postdoctoral Innovation Practice Base, The First Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China.
Cellular Signalling +

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October 22, 2024

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October 22, 2024

View abstract on PubMed

Summary

This summary is machine-generated.

Ring Finger Protein 31 (RNF31) promotes ulcerative colitis (UC) by degrading NRF2. Reducing RNF31 alleviates colitis in mice by preserving NRF2, suggesting RNF31 as a potential UC therapy.

Area Of Science

  • Gastroenterology
  • Molecular Biology
  • Immunology

Background

  • The role of Ring Finger Protein 31 (RNF31) in ulcerative colitis (UC) pathogenesis remains unclear, despite its known association with inflammatory diseases and colorectal cancer.
  • Understanding RNF31's function is crucial for developing targeted therapies for UC.

Purpose Of The Study

  • To investigate the role of RNF31 in the development of ulcerative colitis (UC).
  • To elucidate the molecular mechanisms by which RNF31 influences intestinal inflammation and barrier integrity.

Main Methods

  • Utilized a dextran sulfate sodium (DSS)-induced mouse model of experimental colitis.
  • Employed in vitro RNF31 silencing and overexpression experiments to assess its impact on colonic mucosal barrier.
  • Conducted immunohistochemistry, in silico analysis, cycloheximide-chase assays, and Co-Immunoprecipitation (Co-IP) to explore RNF31-NRF2-P62 interactions.

Main Results

  • RNF31 expression was significantly elevated in UC patients and inflamed murine colons, inversely correlating with NRF2 levels.
  • RNF31 knockdown ameliorated DSS-induced colitis severity in mice, preserving colon epithelial barrier integrity.
  • RNF31 was found to promote NRF2 degradation via K63 ubiquitination, leading to increased IL1β and IL18 secretion and barrier damage.
  • RNF31 stability was regulated by autophagy, influenced by its interaction with P62.

Conclusions

  • RNF31 exacerbates ulcerative colitis by promoting NRF2 degradation and subsequent inflammatory responses.
  • Inhibition of RNF31 effectively reduces experimental colitis in mice by stabilizing NRF2.
  • RNF31 represents a promising therapeutic target for human ulcerative colitis.

Keywords:

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