ArticleNature cell biology2018
TBK1 and IKKε prevent TNF-induced cell death by RIPK1 phosphorylation.
Article in Nature cell biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 188 papers, 1 of them a synthesis that pooled it.
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Who cites it
188 citing papers in PubMed, 1 synthesis or guideline pooled it, 272 citations in OpenAlex.
- Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target.Nature reviews. Drug discovery · 2020Pooled it
- Transglutaminase 2 regulates innate immunity: mechanisms and therapeutic implications.Oncoimmunology · 2026Review
- Discovery of N8: a novel IKKε inhibitor with potent anticancer activity via cytotoxicity, migration suppression, and autophagy modulation.Journal of enzyme inhibition and medicinal chemistry · 2026Article
- One adaptor, multiple outcomes: decoding TRIFosome heterogeneity.Biochemical Society transactions · 2026Review
- Death domain-mediated higher-order oligomerization of RIPK1 drives TNF-induced signaling.Cell death and differentiation · 2026Article
- Mechanisms, regulation and clinical relevance of necroptosis.Nature reviews. Molecular cell biology · 2026Review
- HERC4-mediated ubiquitination licenses RIPK1 to initiate TNF-induced cell death.Nature structural & molecular biology · 2026Article
- ZBP1 in Neuroinflammation and Neurodegeneration: Z-Nucleic-Acid Sensing, RHIM Signalling and Therapeutic Targeting.International journal of molecular sciences · 2026Review
- AMPK as a central regulator of necroptosis: mechanistic insights and therapeutic implications.Journal of physiology and biochemistry · 2026Review
- Oncogenic EGFR rewires STING-TBK1 signalosomes to license DNA damage tolerance in NSCLC.The EMBO journal · 2026Article
- PANoptosis in the pathogenesis of myelodysplastic syndromes.Molecular oncology · 2026Review
- The dual role of RIPK family in IBD: from cell death to therapeutic targeting.Molecular medicine (Cambridge, Mass.) · 2026Review
- Integrated Necroptosis Within Programmed Cell Death in Traumatic Brain Injury.Molecular neurobiology · 2026Review
- Loss of the kinases TBK1 and IKKε sensitizes target cancer cells to T cell killing through an IFN-γ-mediated inflammatory death program.Science signaling · 2026Article
- Species-specific regulation of necroptosis by STK38-dependent RIPK1 phosphorylation.Cell death and differentiation · 2026Article
- Article
- Selective degradation of TBK1 uncovers mechanistic insights into blocking ccRCC progression.Cell chemical biology · 2026Article
- Machine learning-based predictive models and subtypes patterns in peripheral blood of schizophrenia based on a machine learning computational framework.Schizophrenia (Heidelberg, Germany) · 2026Article
- Lysine-11 ubiquitination drives type-I/III interferon induction by cGAS-STING and Toll-like receptors 3 and 4.Nature cell biology · 2026Article
- ACT001 synergizes with temozolomide-based chemoradiotherapy to cure refractory glioblastoma by targeting TNF-CXCL10-CD8Frontiers in pharmacology · 2026Article
128 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 4 institutions in 3 countries.
Funding
Abstract
The linear-ubiquitin chain assembly complex (LUBAC) modulates signalling via various immune receptors. In tumour necrosis factor (TNF) signalling, linear (also known as M1) ubiquitin enables full gene activation and prevents cell death. However, the mechanisms underlying cell death prevention remain ill-defined. Here, we show that LUBAC activity enables TBK1 and IKKε recruitment to and activation at the TNF receptor 1 signalling complex (TNFR1-SC). While exerting only limited effects on TNF-induced gene activation, TBK1 and IKKε are essential to prevent TNF-induced cell death. Mechanistically, TBK1 and IKKε phosphorylate the kinase RIPK1 in the TNFR1-SC, thereby preventing RIPK1-dependent cell death. This activity is essential in vivo, as it prevents TNF-induced lethal shock. Strikingly, NEMO (also known as IKKγ), which mostly, but not exclusively, binds the TNFR1-SC via M1 ubiquitin, mediates the recruitment of the adaptors TANK and NAP1 (also known as AZI2). TANK is constitutively associated with both TBK1 and IKKε, while NAP1 is associated with TBK1. We discovered a previously unrecognized cell death checkpoint that is mediated by TBK1 and IKKε, and uncovered an essential survival function for NEMO, whereby it enables the recruitment and activation of these non-canonical IKKs to prevent TNF-induced cell death.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.