In TNF-stimulated Cells, RIPK1 Promotes Cell Survival by Stabilizing TRAF2 and cIAP1, which Limits Induction of Non-canonical NF-κB and Activation of Caspase-8
Open accessAbstract
RIPK1 is involved in signaling from TNF and TLR family receptors. After receptor ligation, RIPK1 not only modulates activation of both canonical and NIK-dependent NF-κB, but also regulates caspase-8 activation and cell death. Although overexpression of RIPK1 can cause caspase-8-dependent cell death, when RIPK1(-/-) cells are exposed to TNF and low doses of cycloheximide, they die more readily than wild-type cells, indicating RIPK1 has pro-survival as well as pro-apoptotic activities. To determine how RIPK1 promotes cell survival, we compared wild-type and RIPK1(-/-) cells treated with TNF. Although TRAF2 levels remained constant in TNF-treated wild-type cells, TNF stimulation of RIPK1(-/-) cells caused TRAF2 and cIAP1 to be rapidly degraded by the proteasome, which led to an increase in NIK levels. This resulted in processing of p100 NF-κB2 to p52, a decrease in levels of cFLIP(L), and activation of caspase-8, culminating in cell death. Therefore, the pro-survival effect of RIPK1 is mediated by stabilization of TRAF2 and cIAP1.
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Proteasomal degradation of TRAF2 appears to be prevented (at least in hepatocytes) by RIPK1, independently of its kinase activity.
“To add a further layer of complexity, the proteasomal degradation of TRAF2 appears to be prevented (at least in hepatocytes) by RIPK1, independently of its kinase activity [340, 341].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [341]
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References 40 · Cited by 96
- Authors
- Gentle, I. E., Wong, W. W.-L., Evans, J. M., Bankovacki, A., Cook, W. D., Khan, N. R., Nachbur, U., Rickard, J., Anderton, H., Moulin, M., Lluis, J. M., Moujalled, D. M., Silke, J., & Vaux, D. L.
- Affiliations
- La Trobe University (AU)
- Corresponding author
- Vaux, David L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 286
- Issue
- 15
- Pages
- 13282-13291
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3075675
- OpenAlex
- W2080548340
- Cited by
- 96
- References
- 40
- Citations by year
- 2025: 4 · 2024: 4 · 2023: 2 · 2022: 3 · 2020: 3 · 2019: 5 · 2018: 9 · 2017: 11 · 2016: 14 · 2015: 10 · 2014: 12 · 2013: 10 · 2012: 3
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Update notices
- correction (2016-01-29)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Keywords
- RIPK1, TRAF2, cIAP1, TNF signaling, cell survival, non-canonical NF-κB, NIK, caspase-8 activation, proteasomal degradation, apoptosis
- MeSH terms
- NF-kappaB-Inducing Kinase, Animals, Cell Survival, Cycloheximide, Enzyme Activation, Protein Synthesis Inhibitors, Tumor Necrosis Factor-alpha, NF-kappa B, Cell Death, Protein Serine-Threonine Kinases, Mice, Knockout, Proteasome Endopeptidase Complex, TNF Receptor-Associated Factor 2, Inhibitor of Apoptosis Proteins, Mice, Caspase 8, Receptor-Interacting Protein Serine-Threonine Kinases, Protein Stability
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