ArticleProceedings of the National Academy of Sciences of the United States of America2021
TBK1 and IKKε act like an OFF switch to limit NLRP3 inflammasome pathway activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers, 1 of them a synthesis that pooled it.
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Who cites it
31 citing papers in PubMed, 1 synthesis or guideline pooled it, 38 citations in OpenAlex.
- mRNA expression of NLRP3 and IL1B in inflammatory bowel diseases: a systematic review and meta-analysis.BMC gastroenterology · 2025Pooled it
- Cell Type-Specific Roles of TBK1 in Steatotic Liver Disease: Evidence for an Inflammatory TBK1Liver international : official journal of the International Association for the Study of the Liver · 2026Article
- Article
- Molecular mechanisms of NLRP3 inflammasome activation.Experimental & molecular medicine · 2026Review
- Post-translational modifications of NLRP3: to prime or not to prime?Trends in immunology · 2026Review
- Minding the gates: dual cell-autonomous and non-cell-autonomous mechanisms of TBK1 in ALS/FTD.Frontiers in neuroscience · 2026Review
- Mitochondrial DNA efflux as a potential amplifier of systemic inflammatory network rewiring in heart failure with preserved ejection fraction.Frontiers in immunology · 2026Review
- Hepatocyte-Derived Extracellular Vesicles Deliver miR-328-3p to Trigger PP2A-B56δ-Mediated p-NLRP3Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Toll-like receptors in innate immunity and inflammation: from fundamental biology to clinic insights.Immunity & inflammation · 2026Review
- STING agonists trigger monocyte death via apoptosis, pyroptosis, caspase-8 activation and mitochondrial dysfunction.Cell death discovery · 2025Article
- Updated insights into the molecular networks for NLRP3 inflammasome activation.Cellular & molecular immunology · 2025Review
- TBK1 and IKKε prevent premature cell death by limiting the activity of both RIPK1 and NLRP3 death pathways.Science advances · 2025Article
- HDAC10 switches NLRP3 modification from acetylation to ubiquitination and attenuates acute inflammatory diseases.Cell communication and signaling : CCS · 2024Article
- Emerging roles of TBK1 in cancer immunobiology.Trends in cancer · 2024Review
- Spatiotemporal proteomic profiling of cellular responses to NLRP3 agonists.bioRxiv : the preprint server for biology · 2024Article
- Functional Involvement of TANK-Binding Kinase 1 in the MyD88-Dependent NF-Mediators of inflammation · 2024Article
- IKBKE regulates renal cell carcinoma progression and sunitinib resistance through the RRM2-AKT pathway.International journal of biological sciences · 2024Article
- Targeting NLRP3 inflammasome for neurodegenerative disorders.Molecular psychiatry · 2023Review
- The ion channel CALHM6 controls bacterial infection-induced cellular cross-talk at the immunological synapse.The EMBO journal · 2023Article
- The NLRP3 inflammasome: activation and regulation.Trends in biochemical sciences · 2023Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
Abstract
NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation is beneficial during infection and vaccination but, when uncontrolled, is detrimental and contributes to inflammation-driven pathologies. Hence, discovering endogenous mechanisms that regulate NLRP3 activation is important for disease interventions. Activation of NLRP3 is regulated at the transcriptional level and by posttranslational modifications. Here, we describe a posttranslational phospho-switch that licenses NLRP3 activation in macrophages. The ON switch is controlled by the protein phosphatase 2A (PP2A) downstream of a variety of NLRP3 activators in vitro and in lipopolysaccharide-induced peritonitis in vivo. The OFF switch is regulated by two closely related kinases, TANK-binding kinase 1 (TBK1) and I-kappa-B kinase epsilon (IKKε). Pharmacological inhibition of TBK1 and IKKε, as well as simultaneous deletion of TBK1 and IKKε, but not of either kinase alone, increases NLRP3 activation. In addition, TBK1/IKKε inhibitors counteract the effects of PP2A inhibition on inflammasome activity. We find that, mechanistically, TBK1 interacts with NLRP3 and controls the pathway activity at a site distinct from NLRP3-serine 3, previously reported to be under PP2A control. Mutagenesis of NLRP3 confirms serine 3 as an important phospho-switch site but, surprisingly, reveals that this is not the sole site regulated by either TBK1/IKKε or PP2A, because all retain the control over the NLRP3 pathway even when serine 3 is mutated. Altogether, a model emerges whereby TLR-activated TBK1 and IKKε act like a "parking brake" for NLRP3 activation at the time of priming, while PP2A helps remove this parking brake in the presence of NLRP3 activating signals, such as bacterial pore-forming toxins or endogenous danger signals.
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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.