| First Author | Fujita Y | Year | 2018 |
| Journal | Cell Rep | Volume | 24 |
| Issue | 12 | Pages | 3296-3311.e6 |
| PubMed ID | 30232010 | Mgi Jnum | J:270895 |
| Mgi Id | MGI:6278338 | Doi | 10.1016/j.celrep.2018.08.057 |
| Citation | Fujita Y, et al. (2018) Regulation of S100A8 Stability by RNF5 in Intestinal Epithelial Cells Determines Intestinal Inflammation and Severity of Colitis. Cell Rep 24(12):3296-3311.e6 |
| abstractText | 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. |
