Journal
NATURE IMMUNOLOGY
Volume 16, Issue 6, Pages 618-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.3172
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Funding
- Biomedical Technology Research Centers program of the National Institute of General Medical Sciences of the US National Institutes of Health [8P41GM103481]
- Howard Hughes Medical Institute
- US National Institutes of Health [DK071939, DK095693, AI073737, NS063008]
- Kenneth Rainin Foundation
- National Multiple Sclerosis Society [RG 4768, RG 5180]
- Guthy Jackson Charitable Foundation
- Maisin Foundation
- Crohn's and Colitis Foundation of America
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A20 is an anti-inflammatory protein linked to multiple human diseases; however, the mechanisms by which A20 prevents inflammatory disease are incompletely defined. We found that A20-deficient T cells and fibroblasts were susceptible to caspase-independent and kinase RIPK3-dependent necroptosis. Global deficiency in RIPK3 significantly restored the survival of A20-deficient mice. A20-deficient cells exhibited exaggerated formation of RIPK1-RIPK3 complexes. RIPK3 underwent physiological ubiquitination at Lys5 (K5), and this ubiquitination event supported the formation of RIPK1-RIPK3 complexes. Both the ubiquitination of RIPK3 and formation of the RIPK1-RIPK3 complex required the catalytic cysteine of A20's deubiquitinating motif. Our studies link A20 and the ubiquitination of RIPK3 to necroptotic cell death and suggest additional mechanisms by which A20 might prevent inflammatory disease.
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