Regulation of S100A8 Stability by RNF5 in Intestinal Epithelial Cells Determines Intestinal Inflammation and Severity of Colitis

Cell Rep. 2018 Sep 18;24(12):3296-3311.e6. doi: 10.1016/j.celrep.2018.08.057.


Inflammatory bowel disease (IBD) is prevalent, but the mechanisms underlying disease development remain elusive. We identify a role for the E3 ubiquitin ligase RNF5 in IBD. Intestinal epithelial cells (IECs) express a high level of RNF5, while the colon of Rnf5-/- mice exhibits activated dendritic cells and intrinsic inflammation. Rnf5-/- mice exhibit severe acute colitis following dextran sodium sulfate (DSS) treatment. S100A8 is identified as an RNF5 substrate, resulting in S100A8 ubiquitination and proteasomal-dependent degradation that is attenuated upon inflammatory stimuli. Loss of RNF5 from IECs leads to enhanced S100A8 secretion, which induces mucosal CD4+ T cells, resulting in Th1 pro-inflammatory responses. Administration of S100A8-neutralizing antibodies to DSS-treated Rnf5-/- mice attenuates acute colitis development and increases survival. An inverse correlation between RNF5 and S100A8 protein expression in IECs of IBD patients coincides with disease severity. Collectively, RNF5-mediated regulation of S100A8 stability in IECs is required for the maintenance of intestinal homeostasis.

Keywords: IBD; RNF5; S100A8; acute colitis; intestinal epithelial cells; intestinal inflammation; ubiquitin ligase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / therapeutic use
  • CD4-Positive T-Lymphocytes / immunology
  • Calgranulin A / immunology
  • Calgranulin A / metabolism*
  • Cell Line
  • Cells, Cultured
  • Colitis, Ulcerative / drug therapy
  • Colitis, Ulcerative / metabolism*
  • Enterocytes / metabolism*
  • HEK293 Cells
  • Humans
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Protein Stability
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism


  • Antibodies, Neutralizing
  • Calgranulin A
  • Membrane Proteins
  • S100a8 protein, mouse
  • RNF5 protein, mouse
  • Ubiquitin-Protein Ligases