Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death
dc.contributor.author | Garcia-Carbonell, Ricard | |
dc.contributor.author | Wong, Jerry | |
dc.contributor.author | Kim, Ju Youn | |
dc.contributor.author | Close, Lisa Abernathy | |
dc.contributor.author | Boland, Brigid S. | |
dc.contributor.author | Wong, Thomas L. | |
dc.contributor.author | Harris, Philip A. | |
dc.contributor.author | Ho, Samuel B. | |
dc.contributor.author | Das, Soumita | |
dc.contributor.author | Ernst, Peter B. | |
dc.contributor.author | Sasik, Roman | |
dc.contributor.author | Sandborn, William J. | |
dc.contributor.author | Bertin, John | |
dc.contributor.author | Gough, Pete J. | |
dc.contributor.author | Chang, John T. | |
dc.contributor.author | Kelliher, Michelle | |
dc.contributor.author | Boone, David | |
dc.contributor.author | Guma, Monica | |
dc.contributor.author | Karin, Michael | |
dc.contributor.department | Microbiology and Immunology, School of Medicine | en_US |
dc.date.accessioned | 2019-08-14T14:04:03Z | |
dc.date.available | 2019-08-14T14:04:03Z | |
dc.date.issued | 2018-09-25 | |
dc.description.abstract | Intestinal 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_US |
dc.eprint.version | Final published version | en_US |
dc.identifier.citation | Garcia-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.1810584115 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/20354 | |
dc.language.iso | en_US | en_US |
dc.publisher | National Academy of Sciences | en_US |
dc.relation.isversionof | 10.1073/pnas.1810584115 | en_US |
dc.relation.journal | Proceedings of the National Academy of Sciences of the United States of America | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | PMC | en_US |
dc.subject | A20 | en_US |
dc.subject | RIPK1 | en_US |
dc.subject | Apoptosis | en_US |
dc.subject | Inflammatory bowel disease | en_US |
dc.subject | Intestinal epithelial cells | en_US |
dc.title | Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death | en_US |
dc.type | Article | en_US |