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

ABSTRACT: 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 an

SUBMITTER: Fujita Y 

PROVIDER: S-EPMC6185744 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature