Journal Article

Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death

Boland, Brigid S., Boone, David, Karin, Michael, Kim, Ju Youn, Das, Soumita, Harris, Philip A., Bertin, John, Ernst, Peter B., Sasik, Roman, Kelliher, Michelle, Wong, Thomas L., Sandborn, William J., Chang, John T., Garcia-Carbonell, Ricard, Wong, Jerry, Close, Lisa Abernathy, Ho, Samuel B., Guma, Monica, Gough, Pete J.

2018

Overview

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.

• Publisher: National Academy of Sciences
• Subject: A20 protein / Animals / Apoptosis / Biological Sciences / Caspase / Caspase 3 - genetics / Caspase 3 - metabolism / Caspase 8 - genetics / Caspase 8 - metabolism / Caspase-3 / Caspase-8 / Cell death / Deaths / Digestive system / Dimerization / Dimers / Epithelial cells / Epithelium / Fibroblasts / Gene expression / Humans / Inflammation / Inflammatory bowel diseases / Inflammatory Bowel Diseases - genetics / Inflammatory Bowel Diseases - metabolism / Inflammatory Bowel Diseases - pathology / Intestinal Mucosa - metabolism / Intestinal Mucosa - pathology / Intestine / Irritable bowel syndrome / Medical Sciences / Mice / Mice, Transgenic / Mortality / Negative feedback / NF-kappa B - genetics / NF-kappa B - metabolism / NF-κB protein / Organoids / Patients / PNAS Plus / Protein kinase / Protein Multimerization / Proteins / Receptor-Interacting Protein Serine-Threonine Kinases - genetics / Receptor-Interacting Protein Serine-Threonine Kinases - metabolism / Transgenic mice / Tumor necrosis factor / Tumor Necrosis Factor alpha-Induced Protein 3 - genetics / Tumor Necrosis Factor alpha-Induced Protein 3 - metabolism / Tumor Necrosis Factor-alpha - genetics / Tumor Necrosis Factor-alpha - metabolism / Ubiquitin / Zinc finger proteins