ArticleProceedings of the National Academy of Sciences of the United States of America2017
Roles of the TRAF6 and Pellino E3 ligases in MyD88 and RANKL signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 125 citations in OpenAlex.
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- Golgi-associated TRAF6 as a regulator of protein convertase FURIN for insulin receptor precursor processing.Science China. Life sciences · 2025Article
- The Ubiquitin-Proteasome System in Brain Disorders: Pathogenic Pathways, Post-Translational Tweaks, and Therapeutic Frontiers.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2025Review
- TRAF6 regulates ubiquitination-independent TDP-43 condensation and related neurodegeneration.Molecular psychiatry · 2025Article
- IRAK signaling in cancers: mechanisms, targeting, and clinical implications.Expert opinion on investigational drugs · 2025Review
- Regulation of toll-like receptor signaling pathways in age-related eye disease: from mechanisms to targeted therapeutics.Inflammopharmacology · 2025Review
- Neutrophil diversity and function in health and disease.Signal transduction and targeted therapy · 2024Review
- REGγ is essential to maintain bone homeostasis by degrading TRAF6, preventing osteoporosis.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- A ubiquitin-specific, proximity-based labeling approach for the identification of ubiquitin ligase substrates.Science advances · 2024Article
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- OTUD5 promotes the inflammatory immune response by enhancing MyD88 oligomerization and Myddosome formation.Cell death and differentiation · 2024Article
- Dysregulation of innate immune signaling in animal models of spinal muscular atrophy.BMC biology · 2024Article
- Unveiling the multifaceted role of toll-like receptors in immunity of aquatic animals: pioneering strategies for disease management.Frontiers in immunology · 2024Review
- Dysregulation of innate immune signaling in animal models of Spinal Muscular Atrophy.bioRxiv : the preprint server for biology · 2023Article
- ALPK1 mutants causing ROSAH syndrome or Spiradenoma are activated by human nucleotide sugars.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- The OX40-TRAF6 axis promotes CTLA-4 degradation to augment antitumor CD8Cellular & molecular immunology · 2023Article
9 more citing papers are in PubMed but not listed here.
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12 authors at 2 institutions in 2 countries.
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Abstract
It is widely accepted that the essential role of TRAF6 in vivo is to generate the Lys63-linked ubiquitin (K63-Ub) chains needed to activate the "master" protein kinase TAK1. Here, we report that TRAF6 E3 ligase activity contributes to but is not essential for the IL-1-dependent formation of K63-Ub chains, TAK1 activation, or IL-8 production in human cells, because Pellino1 and Pellino2 generate the K63-Ub chains required for signaling in cells expressing E3 ligase-inactive TRAF6 mutants. The IL-1-induced formation of K63-Ub chains and ubiquitylation of IRAK1, IRAK4, and MyD88 was abolished in TRAF6/Pellino1/Pellino2 triple-knockout (KO) cells, but not in TRAF6 KO or Pellino1/2 double-KO cells. The reexpression of E3 ligase-inactive TRAF6 mutants partially restored IL-1 signaling in TRAF6 KO cells, but not in TRAF6/Pellino1/Pellino2 triple-KO cells. Pellino1-generated K63-Ub chains activated the TAK1 complex in vitro with similar efficiently to TRAF6-generated K63-Ub chains. The early phase of TLR signaling and the TLR-dependent secretion of IL-10 (controlled by IRAKs 1 and 2) was only reduced modestly in primary macrophages from knockin mice expressing the E3 ligase-inactive TRAF6[L74H] mutant, but the late-phase production of IL-6, IL-12, and TNFα (controlled only by the pseudokinase IRAK2) was abolished. RANKL-induced signaling in macrophages and the differentiation of bone marrow to osteoclasts was similar in TRAF6[L74H] and wild-type cells, explaining why the bone structure and teeth of the TRAF6[L74H] mice was normal, unlike TRAF6 KO mice. We identify two essential roles of TRAF6 that are independent of its E3 ligase activity.
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