ArticleThe Journal of biological chemistry2018
Mechanism of dysfunction of human variants of the IRAK4 kinase and a role for its kinase activity in interleukin-1 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 22 papers.
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Who cites it
22 citing papers in PubMed, 44 citations in OpenAlex.
- 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
- A heterobifunctional IRAK4-targeting degrader impairs myddosome signaling in acute kidney injury and ameliorates kidney fibrosis.Communications biology · 2026Article
- Review
- IRAK4: potential therapeutic target for airway disease exacerbations.Trends in pharmacological sciences · 2025Article
- Structural and dynamic properties of IL1 receptors.Frontiers in immunology · 2025Review
- Emerging interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors or degraders as therapeutic agents for autoimmune diseases and cancer.Acta pharmaceutica Sinica. B · 2024Review
- Novel Approaches to Managing Patients with Relapsed and Refractory Waldenström Macroglobulinemia.Current hematologic malignancy reports · 2024Review
- Genetic diversity of United States Rambouillet, Katahdin and Dorper sheep.Genetics, selection, evolution : GSE · 2024Article
- A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease.Molecules (Basel, Switzerland) · 2024Article
- Induced protein degradation for therapeutics: past, present, and future.The Journal of clinical investigation · 2024Review
- Metabolic changes in fibroblast-like synoviocytes in rheumatoid arthritis: state of the art review.Frontiers in immunology · 2024Review
- A noncanonical IRAK4-IRAK1 pathway counters DNA damage-induced apoptosis independently of TLR/IL-1R signaling.Science signaling · 2023Article
- IRAK4 inhibition: an effective strategy for immunomodulating peri-implant osseointegration via reciprocally-shifted polarization in the monocyte-macrophage lineage cells.BMC oral health · 2023Article
- Regulation of innate immune signaling by IRAK proteins.Frontiers in immunology · 2023Review
- The IRAK4 scaffold integrates TLR4-driven TRIF and MYD88 signaling pathways.Cell reports · 2022Article
- Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model.Arthritis research & therapy · 2021Article
- Protein phosphatases in TLR signaling.Cell communication and signaling : CCS · 2021Review
- Design, Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs.ACS medicinal chemistry letters · 2021Article
- Kinase inhibition in autoimmunity and inflammation.Nature reviews. Drug discovery · 2021Review
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Interleukin-1 receptor (IL1R)-associated kinase 4 (IRAK4) is a central regulator of innate immune signaling, controlling IL1R and Toll-like receptor (TLR)-mediated responses and containing both scaffolding and kinase activities. Humans deficient in IRAK4 activity have autosomal recessive primary immune deficiency (PID). Here, we characterized the molecular mechanism of dysfunction of two IRAK4 PID variants, G298D and the compound variant R12C (R12C/R391H/T458I). Using these variants and the kinase-inactive D329A variant to delineate the contributions of IRAK4's scaffolding and kinase activities to IL1R signaling, we found that the G298D variant is kinase-inactive and expressed at extremely low levels, acting functionally as a null mutation. The R12C compound variant possessed WT kinase activity, but could not interact with myeloid differentiation primary response 88 (MyD88) and IRAK1, causing impairment of IL-1-induced signaling and cytokine production. Quantitation of IL-1 signaling in IRAK4-deficient cells complemented with either WT or the R12C or D329A variant indicated that the loss of MyD88 interaction had a greater impact on IL-1-induced signaling and cytokine expression than the loss of IRAK4 kinase activity. Importantly, kinase-inactive IRAK4 exhibited a greater association with MyD88 and a weaker association with IRAK1 in IRAK4-deficient cells expressing kinase-inactive IRAK4 and in primary cells treated with a selective IRAK4 inhibitor. Loss of IRAK4 kinase activity only partially inhibited IL-1-induced cytokine and NF-κB signaling. Therefore, the IRAK4-MyD88 scaffolding function is essential for IL-1 signaling, but IRAK4 kinase activity can control IL-1 signal strength by modulating the association of IRAK4, MyD88, and IRAK1.
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