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Proc Natl Acad Sci U S A. 2018 Sep 25;115(39):E9192-E9200. doi: 10.1073/pnas.1810584115. Epub 2018 Sep 12.

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

Author information

1
Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, CA 92093.
2
Department of Pharmacology, University of California, San Diego, CA 92093.
3
Department of Pathology, University of California, San Diego, CA 92093.
4
Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
5
Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, IN 46617.
6
Department of Medicine, Division of Gastroenterology, University of California, San Diego, CA 92093.
7
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426.
8
Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161.
9
Center for Computational Biology, University of California, San Diego, CA 92093.
10
Institute for Genomic Medicine, University of California, San Diego, CA 92093.
11
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605.
12
Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, CA 92093; mguma@ucsd.edu karinoffice@ucsd.edu.
13
Department of Medicine, Division of Rheumatology, University of California, San Diego, CA 92093.
14
Department of Medicine, Autonomous University of Barcelona, 08193 Bellaterra, Barcelona, Spain.

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.

KEYWORDS:

A20; RIPK1; apoptosis; inflammatory bowel disease; intestinal epithelial cells

PMID:
30209212
PMCID:
PMC6166836
DOI:
10.1073/pnas.1810584115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: P.A.H., J.B., and P.J.G. are employees and shareholders of GlaxoSmithKline. The remaining authors declare no competing financial interests.

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