NF-κB-Independent Role of IKKα/IKKβ in Preventing RIPK1 Kinase-Dependent Apoptotic and Necroptotic Cell Death during TNF Signaling
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TNF is a master pro-inflammatory cytokine. Activation of TNFR1 by TNF can result in both RIPK1-independent apoptosis and RIPK1 kinase-dependent apoptosis or necroptosis. These cell death outcomes are regulated by two distinct checkpoints during TNFR1 signaling. TNF-mediated NF-κB-dependent induction of pro-survival or anti-apoptotic molecules is a well-known late checkpoint in the pathway, protecting cells from RIPK1-independent death. On the other hand, the molecular mechanism regulating the contribution of RIPK1 to cell death is far less understood. We demonstrate here that the IKK complex phosphorylates RIPK1 at TNFR1 complex I and protects cells from RIPK1 kinase-dependent death, independent of its function in NF-κB activation. We provide in vitro and in vivo evidence that inhibition of IKKα/IKKβ or its upstream activators sensitizes cells to death by inducing RIPK1 kinase-dependent apoptosis or necroptosis. We therefore report on an unexpected, NF-κB-independent role for the IKK complex in protecting cells from RIPK1-dependent death downstream of TNFR1.
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Assembly of necrosome upon TNFR1 stimulation impinges on two conditions: pharmacological or genetic CASP8 inactivation, and RIPK1 deubiquitination-dependent phosphorylation (at least in some settings), which can be favored by SMAC mimetics.
“In addition, the assembly of the necrosome upon TNFR1 stimulation impinges on two conditions: (1) pharmacological or genetic CASP8 inactivation [478, 479], and (2) RIPK1 deubiquitination-dependent phosphorylation (at least in some settings), which can be favored by exogenously provided SMAC mimetics, ensuring the release of RIPK1 from complex I (see above) [334, 335, 480, 481].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [335]
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Cites
Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes
Micheau, O., & Tschopp, J. (2003) · Cell · doi:10.1016/s0092-8674(03)00521-x · Cited by 2,738 · see citing works
Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-α
He, S., Wang, L., Miao, L., Wang, T., Du, F., Zhao, L., & Wang, X. (2009) · Cell · doi:10.1016/j.cell.2009.05.021 · Cited by 2,214 · see citing works
IAPs limit activation of RIP kinases by TNF receptor 1 during development
Moulin, M., Anderton, H., Voss, A. K., Thomas, T., Wong, W. W., Bankovacki, A., Feltham, R., Chau, D., Cook, W. D., Silke, J., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.18 · Cited by 193 · see citing works
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Research works printed but not linked: 4
- Legarda-Addison, D., Hase, H., O'Donnell, M.A., and Ting, A.T. (2009). NEMO/ IKKgamma regulates an early NF-kappaB-independent cell-death checkpoint during TNF signaling. Cell Death Differ. 16, 1279-1288.
- Mahoney, D.J., Cheung, H.H., Mrad, R.L., Plenchette, S., Simard, C., Enwere, E., Arora, V., Mak, T.W., Lacasse, E.C., Waring, J., and Korneluk, R.G. (2008). Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation. Proc. Natl. Acad. Sci. USA 105, 11778-11783.
- O'Donnell, M.A., Legarda-Addison, D., Skountzos, P., Yeh, W.C., and Ting, A.T. (2007). Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling. Curr. Biol. 17, 418-424.
- Zhao, J., Jitkaew, S., Cai, Z., Choksi, S., Li, Q., Luo, J., and Liu, Z.G. (2012). Mixed lineage kinase domain-like is a key receptor interacting protein 3 down- stream component of TNF-induced necrosis. Proc. Natl. Acad. Sci. USA 109, 5322-5327.
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Self-citationNecroptosis in development, inflammation and disease
Weinlich, R., Oberst, A., Beere, H. M., & Green, D. R. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.149 · Cited by 1,016 · see citing works
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Grootjans, S., Vanden Berghe, T., & Vandenabeele, P. (2017) · Cell Death & Differentiation · doi:10.1038/cdd.2017.65 · Cited by 566 · see citing works
Self-citationTBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging
Xu, D., Jin, T., Zhu, H., Chen, H., Ofengeim, D., Zou, C., Mifflin, L., Pan, L., Amin, P., Li, W., et al. (2018) · Cell · doi:10.1016/j.cell.2018.07.041 · Cited by 461 · see citing works
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Geng, J., Ito, Y., Shi, L., Amin, P., Chu, J., Ouchida, A. T., Mookhtiar, A. K., Zhao, H., Xu, D., Shan, B., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00406-w · Cited by 325 · see citing works
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Lafont, E., Draber, P., Rieser, E., Reichert, M., Kupka, S., de Miguel, D., Draberova, H., von Mässenhausen, A., Bhamra, A., Henderson, S., et al. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0229-6 · Cited by 283 · see citing works
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Giampazolias, E., Zunino, B., Dhayade, S., Bock, F., Cloix, C., Cao, K., Roca, A., Lopez, J., Ichim, G., Proïcs, E., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3596 · Cited by 258 · see citing works
Rojas-Rivera, D., Delvaeye, T., Roelandt, R., Nerinckx, W., Augustyns, K., Vandenabeele, P., & Bertrand, M. J. M. (2017) · Cell Death & Differentiation · doi:10.1038/cdd.2017.58 · Cited by 206 · see citing works
Self-citationVlantis, K., Wullaert, A., Polykratis, A., Kondylis, V., Dannappel, M., Schwarzer, R., Welz, P., Corona, T., Walczak, H., Weih, F., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.02.020 · Cited by 189 · see citing works
Poly-ubiquitination in TNFR1-mediated necroptosis
Dondelinger, Y., Darding, M., Bertrand, M. J. M., & Walczak, H. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2191-4 · Cited by 173 · see citing works
Self-citationA20 and cell death-driven inflammation
Priem, D., van Loo, G., & Bertrand, M. J. M. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.03.001 · Cited by 139 · see citing works
Self-citationCai, X., Cao, C., Li, J., Chen, F., Zhang, S., Liu, B., Zhang, W., Zhang, X., & Ye, L. (2017) · Oncotarget · doi:10.18632/oncotarget.16873 · Cited by 111 · see citing works
Linear ubiquitination at a glance
Spit, M., Rieser, E., & Walczak, H. (2019) · Journal of Cell Science · doi:10.1242/jcs.208512 · Cited by 94 · see citing works
Molecular mechanisms of necroptosis and relevance for neurodegenerative diseases.
(2020) · International Review of Cell and Molecular Biology · doi:10.1016/bs.ircmb.2019.12.006 · Cited by 51 · see citing works
- Authors
- Dondelinger, Y., Jouan-Lanhouet, S., Divert, T., Theatre, E., Bertin, J., Gough, P. J., Giansanti, P., Heck, A. J. R., Dejardin, E., Vandenabeele, P., & Bertrand, M. J. M.
- Affiliations
- Ghent University (BE)
- GlaxoSmithKline (United States) (US)
- Utrecht University (NL)
- University of Liège (BE)
- Corresponding author
- Bertrand, Mathieu J.M.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 60
- Issue
- 1
- Pages
- 63-76
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2129627069
- Cited by
- 431
- References
- 3
- Citations by year
- 2026: 25 · 2025: 32 · 2024: 37 · 2023: 40 · 2022: 54 · 2021: 38 · 2020: 48 · 2019: 47 · 2018: 37 · 2017: 43 · 2016: 28 · 2015: 2
- FWCI
- 15.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- ORBi (University of Liège) (submittedVersion, other-oa)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- GlaxoSmithKline
- European Commission (262067)
- Fonds Wetenschappelijk Onderzoek (G013715N, G078713N, G017212N)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (184.032.201)
- Universiteit Gent (262067, 01M00709)
- Universiteit Antwerpen
- Fondation contre le Cancer
- Genentech
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Keywords
- RIPK1, TNF signaling, TNFR1, necroptosis, apoptosis, NF-κB-independent signaling, cell death regulation
- MeSH terms
- Animals, Cell Line, Embryo, Mammalian, Fibroblasts, Phosphorylation, Tumor Necrosis Factor-alpha, Signal Transduction, NF-kappa B, Cell Death, Receptors, Tumor Necrosis Factor, Type I, Mice, I-kappa B Kinase, Caspase 8, Fas-Associated Death Domain Protein, Receptor-Interacting Protein Serine-Threonine Kinases
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