ArticleThe Journal of biological chemistry2018
Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a dual role in myddosome formation and Toll-like receptor signaling.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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Who cites it
81 citing papers in PubMed, 141 citations in OpenAlex.
- Pharmacokinetics and Pharmacodynamics of KT-474, a Novel Selective Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) Degrader, in Healthy Adults.Clinical and translational science · 2025Trial
- IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial.Nature medicine · 2023Trial
- The Interleukin-1 Receptor-Associated Kinase 4 Inhibitor PF-06650833 Blocks Inflammation in Preclinical Models of Rheumatic Disease and in Humans Enrolled in a Randomized Clinical Trial.Arthritis & rheumatology (Hoboken, N.J.) · 2021Trial
- IRAK4 autophosphorylation functions as a molecular switch to regulate death domain assembly and Myddosome maturation.Nature communications · 2026Article
- Machine Learning-Driven Drug Repositioning Identifies Putative IRAK4 Inhibitors Through Structure-Based Computational Evaluation.Current issues in molecular biology · 2026Article
- Innate immunity: current understandings and future perspectives.Signal transduction and targeted therapy · 2026Review
- Coronavirus M Protein Hijacks Toll-Interacting Protein (TOLLIP) to Suppress NF-κB Signaling and Promote Immune Evasion.MedComm · 2026Article
- Structural basis for selective and potent degradation of IRAK4 by KT-474.Nature communications · 2026Article
- ROR2 preserves alveolar bone homeostasis by orchestrating IRAK4-dependent suppression of CXCL8-driven osteolysis.Cell communication and signaling : CCS · 2026Article
- Noncanonical IRF3 function mediates STING-dependent pro-inflammatory cytokine production in macrophages.EMBO reports · 2026Article
- A heterobifunctional IRAK4-targeting degrader impairs myddosome signaling in acute kidney injury and ameliorates kidney fibrosis.Communications biology · 2026Article
- Lessons learned in linking PROTACs from discovery to the clinic.Nature reviews. Chemistry · 2026Review
- Renal macrophage TLR7 signaling in lupus nephritis: from pathogenic mechanisms to therapeutic opportunities.Frontiers in immunology · 2026Review
- Placenta-derived extracellular vesicles in maternal plasma of Hb Bart's fetuses.Scientific reports · 2025Article
- An atlas of ferroptosis-induced secretomes.Cell death and differentiation · 2025Article
- Early diagnosis and targeted intervention based on the pathogenesis of rapidly progressive osteoarthritis of the hip.World journal of orthopedics · 2025Review
- Role for IRAK-4 and p38 in Neutrophil Signaling in Response to Bacterial Lipoproteins from Staphylococcus aureus.Inflammation · 2025Article
- Pattern recognition receptors and inflammasome: Now and beyond.Molecules and cells · 2025Review
- Pattern recognition receptors: function, regulation and therapeutic potential.Signal transduction and targeted therapy · 2025Review
- Review
21 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
Abstract
Toll-like receptors (TLRs) form part of the host innate immune system, in which they act as sensors of microbial and endogenous danger signals. Upon TLR activation, the intracellular Toll/interleukin-1 receptor domains of TLR dimers initiate oligomerization of a multiprotein signaling platform comprising myeloid differentiation primary response 88 (MyD88) and members of the interleukin-1 receptor-associated kinase (IRAK) family. Formation of this myddosome complex initiates signal transduction pathways, leading to the activation of transcription factors and the production of inflammatory cytokines. To date, little is known about the assembly and disassembly of the myddosome and about the mechanisms by which these complexes mediate multiple downstream signaling pathways. Here, we isolated myddosome complexes from whole-cell lysates of TLR-activated primary mouse macrophages and from IRAK reporter macrophages to examine the kinetics of myddosome assembly and disassembly. Using a selective inhibitor of IRAK4's kinase activity, we found that whereas TLR cytokine responses were ablated, myddosome formation was stabilized in the absence of IRAK4's kinase activity. Of note, IRAK4 inhibition had only a minimal effect on NF-κB and mitogen-activated protein kinase (MAPK) signaling. In summary, our results indicate that IRAK4 has a critical scaffold function in myddosome formation and that its kinase activity is dispensable for myddosome assembly and activation of the NF-κB and MAPK pathways but is essential for MyD88-dependent production of inflammatory cytokines. Our findings suggest that the scaffold function of IRAK4 may be an attractive target for treating inflammatory and autoimmune diseases.
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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.