ArticleProceedings of the National Academy of Sciences of the United States of America2024
A TLR4/TRAF6-dependent signaling pathway mediates NCoR coactivator complex formation for inflammatory gene activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 15 citations in OpenAlex.
- The impactful role of the HDACs in the regulation of gene expression and as targets for disease therapy.Science advances · 2026Review
- Nuclear receptor coregulator interactions: beyond the switch.Genes & development · 2026Review
- Landscape of NFrontiers in microbiology · 2026Article
- A genome-wide CRISPR screen identifies the TNRC18 gene locus as a regulator of inflammatory signaling.Nature communications · 2025Article
- PGC1α alleviates M1 macrophage polarization through dual regulation of succinate metabolism and TRAF5 expression to mitigate TLR4/NF-κB-driven inflammatory cascades and myocardial ischemia/reperfusion injury.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2025Article
- SMRT anchors the HDAC3 corepressor complex to chromatin to regulate inflammatory and metabolic pathways in macrophages.Nucleic acids research · 2025Article
- Toll-Like Receptors in the Immunotherapy Era: Dual-Edged Swords of Tumor Immunity and Clinical Translation.MedComm · 2025Review
- Nuclear receptors in health and disease: signaling pathways, biological functions and pharmaceutical interventions.Signal transduction and targeted therapy · 2025Review
- Downregulation of the NF-κB protein p65 is a shared phenotype among most anti-aging interventions.GeroScience · 2025Article
- Nonproteolytic ubiquitination regulates chromatin occupancy by the NCoR/SMRT/HDAC3 corepressor complex in MCF-7 breast cancer cells.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Histone chaperones coupled to DNA replication and transcription control divergent chromatin elements to maintain cell fate.Genes & development · 2025Article
- Metabolic Rewiring and Post-Translational Modifications: Unlocking the Mechanisms of Bone Turnover in Osteoporosis.Aging and disease · 2025Review
- Impact of substrate choice on human osteoclast differentiation and secretome: Implications for targeted therapeutic development.PloS one · 2025Article
- The multifaceted role of post-translational modifications in macrophage polarization: from mechanisms to therapeutic targets.Frontiers in immunology · 2025Review
- Functional inversion of circadian regulator REV-ERBα leads to tumorigenic gene reprogramming.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Tricarboxylic Acid Cycle Regulation of Metabolic Program, Redox System, and Epigenetic Remodeling for Bone Health and Disease.Antioxidants (Basel, Switzerland) · 2024Review
- A TLR4/TRAF6-dependent signaling pathway mediates NCoR coactivator complex formation for inflammatory gene activation.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
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Authors and funding
18 authors at 4 institutions in 3 countries.
Funding
Abstract
The nuclear receptor corepressor (NCoR) forms a complex with histone deacetylase 3 (HDAC3) that mediates repressive functions of unliganded nuclear receptors and other transcriptional repressors by deacetylation of histone substrates. Recent studies provide evidence that NCoR/HDAC3 complexes can also exert coactivator functions in brown adipocytes by deacetylating and activating PPARγ coactivator 1α (PGC1α) and that signaling via receptor activator of nuclear factor kappa-B (RANK) promotes the formation of a stable NCoR/HDAC3/PGC1β complex that coactivates nuclear factor kappa-B (NFκB)- and activator protein 1 (AP-1)-dependent genes required for osteoclast differentiation. Here, we demonstrate that activation of Toll-like receptor (TLR) 4, but not TLR3, the interleukin 4 (IL4) receptor nor the Type I interferon receptor, also promotes assembly of an NCoR/HDAC3/PGC1β coactivator complex. Receptor-specific utilization of TNF receptor-associated factor 6 (TRAF6) and downstream activation of extracellular signal-regulated kinase 1 (ERK1) and TANK-binding kinase 1 (TBK1) accounts for the common ability of RANK and TLR4 to drive assembly of an NCoR/HDAC3/PGC1β complex in macrophages. ERK1, the p65 component of NFκB, and the p300 histone acetyltransferase (HAT) are also components of the induced complex and are associated with local histone acetylation and transcriptional activation of TLR4-dependent enhancers and promoters. These observations identify a TLR4/TRAF6-dependent signaling pathway that converts NCoR from a corepressor of nuclear receptors to a coactivator of NFκB and AP-1 that may be relevant to functions of NCoR in other developmental and homeostatic processes.
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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.