Ubiquitination of RIP Is Required for Tumor Necrosis Factor α-induced NF-κB Activation
Open accessAbstract
Stimulation of cells with tumor necrosis factor (TNFalpha) triggers a recruitment of various signaling molecules, such as RIP, to the TNFalpha receptor 1 complex, leading to activation of NF-kappaB. Previous studies indicate that RIP plays an essential role for TNFalpha-induced NF-kappaB activation, but the molecular mechanism by which RIP mediates TNFalpha signals to activate NF-kappaB is not fully defined. Earlier studies suggest that RIP undergoes a ligand-dependent ubiquitination. However, it remains to be determined whether the ubiquitination of RIP is required for TNFalpha-induced NF-kappaB activation. In this study, we have identified Lys377 of RIP as the functional ubiquitination site, because mutating this residue to arginine completely abolished RIP-mediated NF-kappaB activation. The K377R mutation of RIP cannot undergo ligand-dependent ubiquitination and fails to recruit its downstream signaling components into the TNFalpha receptor 1 complex. Together, our studies provide the first genetic evidence that the ubiquitination of RIP is required for TNFalpha-induced NF-kappaB activation.
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TNFR1 activation can have diverse outcomes depending on variables such as post-translational modification status of RIPK1, which impacts assembly of pro-survival vs pro-death signaling complexes.
“In particular, TNFR1 activation can have diverse outcomes depending on multiple variables, such as the post-translational modification status of RIPK1, which has a direct impact on the assembly of pro-survival vs. pro-death signaling complexes [323–325].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [324]
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- Authors
- Li, H., Kobayashi, M., Blonska, M., You, Y., & Lin, X.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Lin, Xin
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-05
- Volume
- 281
- Issue
- 19
- Pages
- 13636-13643
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2124249714
- Cited by
- 277
- References
- 25
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 10 · 2023: 12 · 2022: 13 · 2021: 17 · 2020: 11 · 2019: 8 · 2018: 10 · 2017: 14 · 2016: 10 · 2015: 16 · 2014: 13 · 2013: 11 · 2012: 14
- FWCI
- 8.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (GM065899)
- National Institute of Allergy and Infectious Diseases (AI058048)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Keywords
- RIP, ubiquitination, TNF-α, NF-κB activation, ubiquitination sites, signal transduction
- MeSH terms
- Amino Acid Sequence, Binding Sites, Gene Expression Regulation, Humans, Molecular Sequence Data, Mutation, Tumor Necrosis Factor-alpha, Signal Transduction, NF-kappa B, Protein Serine-Threonine Kinases, Jurkat Cells, Amino Acid Substitution, Ubiquitin, Receptors, Tumor Necrosis Factor, Type I, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Receptor-Interacting Protein Serine-Threonine Kinases
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