The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis
Open accessAbstract
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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Major negative regulators of necrosome include STUB1, A20, PPM1B, and AURKA.
“Major negative regulators of the necrosome include: (1) STIP1 homology and U-box containing protein 1 (STUB1; also known as CHIP), which promotes RIPK1 and RIPK3 ubiquitination followed by lysosomal degradation [472, 473]; (2) A20, which inhibits necrosome assembly by deubiquitinating RIPK3 [473, 474]; (3) protein phosphatase, Mg2+/Mn2+ dependent 1B (PPM1B), which prevents MLKL recruitment to the”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [474]
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- [5]Ma A Malynn BA A20: Linking ubiquitination with immunity and human diseases Nat. Rev. Immunol 2012 12 774 785 23059429 PMC3582397
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- Authors
- Onizawa, M., Oshima, S., Schulze-Topphoff, U., Oses-Prieto, J. A., Lu, T., Tavares, R., Prodhomme, T., Duong, B., Whang, M. I., Advincula, R., Agelidis, A., Barrera, J., Wu, H., Burlingame, A., Malynn, B. A., Zamvil, S. S., & Ma, A.
- Affiliations
- University of California, San Francisco (US)
- Tokyo Medical and Dental University (JP)
- Boston Children's Hospital (US)
- Corresponding author
- Ma, Averil
- ORCID
- Venue
- Nature Immunology
- Published
- 2015-05-04
- Volume
- 16
- Issue
- 6
- Pages
- 618-627
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC4439357
- OpenAlex
- W1542400342
- Cited by
- 284
- References
- 51
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 29 · 2023: 16 · 2022: 31 · 2021: 29 · 2020: 26 · 2019: 27 · 2018: 22 · 2017: 24 · 2016: 30 · 2015: 10
- FWCI
- 12.43
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-06-18)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- National Multiple Sclerosis Society (RG4768, RG 5180)
- Crohn's and Colitis Foundation of America
- Kenneth Rainin Foundation
- National Institutes of Health
- University of California, San Francisco
- National Institute of General Medical Sciences (P41GM103481)
- National Institute of Allergy and Infectious Diseases (R37AI050872, R01AI117908, T32AI007334, R01AI073737, AI073737, R01AI045937)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK071939, DK095693, R01DK095693, DK071939, P30DK042086, P30DK026743, T32DK007007)
- National Institute of Neurological Disorders and Stroke (NS063008, R01NS063008)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- A20, RIPK3, necroptosis, ubiquitination, deubiquitinase, caspase-independent cell death, inflammation, anti-inflammatory mechanism, T cells, fibroblasts
- MeSH terms
- Tumor Necrosis Factor alpha-Induced Protein 3, Animals, Cysteine Endopeptidases, Fibroblasts, Humans, Mice, Inbred C57BL, Necrosis, Protein Binding, T-Lymphocytes, Ubiquitins, Apoptosis, Mice, Knockout, Jurkat Cells, Catalytic Domain, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins, Mice, Receptor-Interacting Protein Serine-Threonine Kinases, Ubiquitination
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