Garcia-Carbonell, RicardWong, JerryKim, Ju YounClose, Lisa AbernathyBoland, Brigid S.Wong, Thomas L.Harris, Philip A.Ho, Samuel B.Das, SoumitaErnst, Peter B.Sasik, RomanSandborn, William J.Bertin, JohnGough, Pete J.Chang, John T.Kelliher, MichelleBoone, DavidGuma, MonicaKarin, Michael2019-08-142019-08-142018-09-25Garcia-Carbonell, R., Wong, J., Kim, J. Y., Close, L. A., Boland, B. S., Wong, T. L., … Karin, M. (2018). Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death. Proceedings of the National Academy of Sciences of the United States of America, 115(39), E9192–E9200. doi:10.1073/pnas.1810584115https://hdl.handle.net/1805/20354Intestinal epithelial cell (IEC) death is a common feature of inflammatory bowel disease (IBD) that triggers inflammation by compromising barrier integrity. In many patients with IBD, epithelial damage and inflammation are TNF-dependent. Elevated TNF production in IBD is accompanied by increased expression of the TNFAIP3 gene, which encodes A20, a negative feedback regulator of NF-κB. A20 in intestinal epithelium from patients with IBD coincided with the presence of cleaved caspase-3, and A20 transgenic (Tg) mice, in which A20 is expressed from an IEC-specific promoter, were highly susceptible to TNF-induced IEC death, intestinal damage, and shock. A20-expressing intestinal organoids were also susceptible to TNF-induced death, demonstrating that enhanced TNF-induced apoptosis was a cell-autonomous property of A20. This effect was dependent on Receptor Interacting Protein Kinase 1 (RIPK1) activity, and A20 was found to associate with the Ripoptosome complex, potentiating its ability to activate caspase-8. A20-potentiated RIPK1-dependent apoptosis did not require the A20 deubiquitinase (DUB) domain and zinc finger 4 (ZnF4), which mediate NF-κB inhibition in fibroblasts, but was strictly dependent on ZnF7 and A20 dimerization. We suggest that A20 dimers bind linear ubiquitin to stabilize the Ripoptosome and potentiate its apoptosis-inducing activity.en-USPublisher PolicyA20RIPK1ApoptosisInflammatory bowel diseaseIntestinal epithelial cellsArticle