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 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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Fujita Y,Khateb A,Li Y,Tinoco R,Zhang T,Bar-Yoseph H,Tam MA,Chowers Y,Sabo E,Gerassy-Vainberg S,Starosvetsky E,James B,Brown K,Shen-Orr SS,Bradley LM,Tessier PA,Ronai ZAdoi
10.1016/j.celrep.2018.08.057subject
Has Abstractpub_date
2018-09-18 00:00:00pages
3296-3311.e6issue
12issn
2211-1247pii
S2211-1247(18)31344-5journal_volume
24pub_type
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