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

Cell Reports
Yu FujitaZe'ev A Ronai

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.

Citations

Nov 21, 2018·Frontiers in Oncology·Dujuan WangYunbao Pan
Mar 23, 2019·Trends in Molecular Medicine·Yu FujitaZe'ev A Ronai
Apr 1, 2020·Journal of Medicinal Chemistry·Xibao TianYongliang Yang
Jul 18, 2021·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Qin YangHongliang Li

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Datasets Mentioned

BETA
PRJNA422424
GM-CSF
GSE14580
GSE12251

Methods Mentioned

BETA
IECs
IEC
ubiquitination
transgenic
biopsies
RNA-seq
FACS
ELISA
flow cytometry
transfection

Software Mentioned

Cufflinks Cuffdiff
R
FlowJo
Hmisc R package
LEGENDplex
Panoramic viewer
BaseSpace
STAR aligner
ComplexHeatmap R
Treestar

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