Affinage

IRAK4

Interleukin-1 receptor-associated kinase 4 · UniProt Q9NWZ3

Length
460 aa
Mass
51.5 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IRAK4 is the apical serine/threonine kinase of the Toll-like receptor (TLR) and IL-1 receptor (IL-1R) innate immune signaling cascade, indispensable in vivo for responses to LPS and microbial challenge (PMID:11923871). Upon receptor engagement, IRAK4 is recruited to the membrane-proximal Myddosome, a left-handed helical death-domain oligomer of 6 MyD88, 4 IRAK4, and 4 IRAK2/IRAK1 subunits assembled hierarchically as MyD88 first recruits IRAK4, which then recruits its IRAK substrates (PMID:20485341). Myddosome-driven dimerization of the IRAK4 kinase domain enables trans-autophosphorylation across the activation loop and is required for ligand-dependent signaling; activation reflects MyD88-induced dimerization rather than a change in intrinsic catalytic activity, since IRAK4 is constitutively active toward Pellino1 in resting cells (PMID:25201411, PMID:28512203). Active IRAK4 phosphorylates and recruits IRAK1, and its substrate repertoire includes Pellino2, the adaptor Mal/TIRAP (driving its ubiquitination and proteasomal degradation as a negative feedback on TLR2/4), and the NADPH oxidase factor p47phox (PMID:15292196, PMID:12860405, PMID:20400509, PMID:17217339). Downstream, IRAK4 nucleates a Pellino1–IRAK–TRAF6 complex bridging the receptor and TAK1, and its kinase activity drives IKKβ-dependent IRF5 activation for inflammatory cytokine transcription (PMID:12496252, PMID:28924041). IRAK4 additionally performs a kinase-independent scaffold function: kinase-inactive IRAK4 retains association with MyD88 and supports NF-κB/MAPK activation and TRAF6 activation from both MyD88- and TRIF-dependent TLR4 arms, while kinase activity primarily tunes signal strength and inflammatory cytokine output (PMID:30115681, PMID:35977521, PMID:30076215, PMID:15084582). IRAK4 activity is downregulated by prolonged TLR stimulation via proteasomal degradation and by induction of negative regulators during endotoxin tolerance (PMID:15258191, PMID:21934070). A U2AF1-mutant splice isoform (IRAK4-L) assembles more efficiently with the Myddosome to drive oncogenic NF-κB signaling in MDS/AML (PMID:31011167).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2002 High

    Established IRAK4 as a non-redundant, essential kinase in innate immunity rather than one of several interchangeable signaling components.

    Evidence Gene-targeted IRAK4-knockout mice challenged with LPS and microbial pathogens

    PMID:11923871

    Open questions at the time
    • Did not resolve whether catalytic activity or scaffolding accounts for the phenotype
    • No molecular structure of how IRAK4 engages the receptor complex
  2. 2002 Medium

    Placed IRAK4 within a defined signal-dependent complex, identifying Pellino1 as a partner bridging the receptor to the TAK1 module.

    Evidence Co-IP and NF-κB/IL-8 reporter assays of a Pellino1–IRAK1–IRAK4–TRAF6 complex

    PMID:12496252

    Open questions at the time
    • No reconstitution or structural validation of complex stoichiometry
    • Direct substrate relationship not established here
  3. 2003 Medium

    Identified Pellino2 as a direct IRAK4 substrate, extending IRAK4's catalytic repertoire beyond the IRAK kinases.

    Evidence Yeast two-hybrid, Co-IP, and in vitro kinase assay showing Pellino2 phosphorylation

    PMID:12860405

    Open questions at the time
    • Phosphosites not mapped
    • Functional consequence of Pellino2 phosphorylation not defined
  4. 2004 High

    Dissected kinase versus scaffold contributions, showing IRAK4 is required to recruit and activate IRAK1 but that kinase-inactive IRAK4 still supports partial signaling.

    Evidence Reciprocal reconstitution of IRAK4-deficient cells with WT vs kinase-inactive IRAK4; NF-κB/JNK and cytokine readouts

    PMID:15084582 PMID:15292196

    Open questions at the time
    • Did not establish in vivo physiological weight of kinase vs scaffold roles
    • Redundancy with IRAK1 kinase activity left the catalytic requirement ambiguous
  5. 2004 Medium

    Revealed that IRAK4 protein levels are actively controlled, linking prolonged TLR signaling to proteasomal turnover of the kinase.

    Evidence Western blot of IRAK4 levels in macrophages after sustained TLR stimulation with proteasome and NF-κB inhibitors

    PMID:15258191

    Open questions at the time
    • Responsible protease/E3 ligase not identified
    • Single cell line; in vivo relevance not tested
  6. 2007 High

    Demonstrated in vivo that IRAK4 catalytic activity is required for TLR-driven inflammation and type I IFN, settling that the kinase function is physiologically essential.

    Evidence IRAK4 kinase-inactive knock-in mice in LPS/CpG shock; pDC IFN and mRNA-stability assays

    PMID:17470642

    Open questions at the time
    • Did not define the direct substrates mediating cytokine mRNA stability
    • Mechanism of IRF/IFN induction not mapped
  7. 2007 High

    Connected IRAK4 to the NADPH oxidase by identifying p47phox as a direct, site-specific substrate, broadening IRAK4 output beyond transcription factors.

    Evidence In vitro kinase assay with MS phosphosite mapping, cell-free oxidase reconstitution, Co-IP and membrane co-localization

    PMID:17217339

    Open questions at the time
    • In vivo contribution of IRAK4-p47phox phosphorylation to oxidative burst not quantified
  8. 2009 Medium

    Extended IRAK4 kinase function to adaptive immunity, showing a T-cell-intrinsic requirement for Th17 differentiation and autoimmunity.

    Evidence Kinase-inactive knock-in mice, Th17 adoptive transfer, and EAE model

    PMID:19542468

    Open questions at the time
    • Direct IRAK4 substrate in T cells not identified
    • Single autoimmune model
  9. 2010 High

    Provided the structural basis for IRAK4 recruitment by resolving the Myddosome as a defined helical death-domain oligomer with hierarchical assembly.

    Evidence X-ray crystallography of the MyD88–IRAK4–IRAK2 death-domain complex with composite-site mutagenesis

    PMID:20485341

    Open questions at the time
    • Did not resolve how kinase domains are activated within the assembled complex
    • Dynamics of assembly/disassembly not captured
  10. 2010 High

    Established a negative-feedback role for IRAK4 catalysis by showing it phosphorylates Mal/TIRAP to trigger its degradation, while excluding MyD88 as a substrate.

    Evidence In vitro kinase, ubiquitination, and LPS-stimulation assays with kinase-inactive mutants and inhibitor/siRNA

    PMID:20400509

    Open questions at the time
    • E3 ligase mediating Mal ubiquitination not identified here
    • Quantitative impact on signal duration not measured
  11. 2014 High

    Defined the activation mechanism, showing Myddosome-driven kinase-domain dimerization positions activation loops for trans-autophosphorylation.

    Evidence Biophysical dimerization assays, crystal structure of the unphosphorylated kinase domain dimer, and signaling assays with dimerization mutants

    PMID:25201411

    Open questions at the time
    • Did not address whether intrinsic catalytic activity changes upon activation
    • Substrate selection in the dimer not defined
  12. 2017 Medium

    Reframed IRAK4 activation as proximity-driven rather than catalysis-switched, showing IRAK4 is constitutively active and activates IRAK1 allosterically.

    Evidence Pellino1 substrate-based kinase assays in cell extracts with selective IRAK1/IRAK4 inhibitors across multiple cell types

    PMID:28512203

    Open questions at the time
    • Cell-extract assay; physiological substrate kinetics not measured
    • Single lab
  13. 2017 Medium

    Identified an IKKβ–IRF5 axis downstream of IRAK4 kinase activity, distinct from canonical NF-κB activation, for TLR7/8 cytokine output.

    Evidence Selective IRAK4 inhibitor in primary human monocytes with IRF5 translocation, ChIP, and IKKβ/TAK1 inhibitor studies

    PMID:28924041

    Open questions at the time
    • No genetic validation of the IRF5 axis
    • Direct IRAK4 substrate upstream of IKKβ not defined
  14. 2018 High

    Established that the IRAK4 scaffold function dominates IL-1 signaling and that kinase activity primarily tunes complex assembly and signal strength.

    Evidence Co-IP of IRAK4 variants with MyD88/IRAK1 and reconstitution/cytokine assays using kinase-dead and MyD88-binding-deficient variants

    PMID:30076215 PMID:30115681

    Open questions at the time
    • Quantitative contribution of scaffold vs kinase across receptors not fully resolved
    • Single lab for each dissection
  15. 2019 High

    Linked IRAK4 to malignancy via a U2AF1-driven splice isoform (IRAK4-L) that hyperassembles with the Myddosome to drive oncogenic NF-κB signaling.

    Evidence Exon-usage analysis, functional isoform expression, NF-κB and leukemic growth assays in patient-derived and mutant models

    PMID:31011167

    Open questions at the time
    • Structural basis of enhanced IRAK4-L Myddosome incorporation not resolved
    • Therapeutic dependence beyond cell models not established
  16. 2019 High

    Characterized the conformational plasticity of unphosphorylated IRAK4, informing type I vs type II inhibitor design.

    Evidence Multiple crystal structures of the unphosphorylated kinase domain bound to AMP-PNP and inhibitors

    PMID:30679311

    Open questions at the time
    • Functional consequence of conformational states in cells not measured
  17. 2022 Medium

    Extended the IRAK4 scaffold requirement to the TRIF arm of TLR4, positioning IRAK4 as an integrator of MyD88- and TRIF-dependent TRAF6 activation.

    Evidence Genetic epistasis in IRAK4-deficient cells plus kinase-inhibitor dissection of TRAF6 activation

    PMID:35977521

    Open questions at the time
    • Mechanism of IRAK4 engagement with the TRIF pathway not defined
    • Single lab; limited orthogonal validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the IRAK4 kinase domain selects among its diverse substrates (IRAK1, Pellino1/2, Mal, p47phox, IRF5) within the Myddosome, and how acetylation and other post-translational modifications regulate IRAK4 in vivo, remain unresolved.
  • Writers/erasers of IRAK4 K34 acetylation and T345/S346 phosphorylation not identified
  • Direct in vitro phosphorylation of IRF5/IRF4 by IRAK4 not demonstrated
  • Rules governing substrate selection in the activated dimer unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0060090 molecular adaptor activity 3 GO:0060089 molecular transducer activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1643685 Disease 2
Partners
IRAK1IRAK2IRF5MYD88PELLINO1PELLINO2TIRAPTRAF6
Complex memberships
Myddosome (MyD88-IRAK4-IRAK2/IRAK1)Pellino1-IRAK-IRAK4-TRAF6 complex

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 Crystal structure of the MyD88-IRAK4-IRAK2 death domain complex reveals a left-handed helical oligomer (Myddosome) comprising 6 MyD88, 4 IRAK4, and 4 IRAK2 death domains. Assembly is hierarchical: MyD88 recruits IRAK4 first, then the MyD88-IRAK4 subcomplex recruits IRAK4 substrates IRAK2 or IRAK1. Composite binding sites mediated by molecular complementarity and surface electrostatics govern specificity. Proximity of recruited IRAK kinase domains enables phosphorylation and activation. X-ray crystallography of ternary death-domain complex; mutagenesis of composite binding sites; functional validation of signaling mutations Nature High 20485341
2002 IRAK-4 is indispensable for IL-1R and TLR signaling in vivo; gene-targeted IRAK-4-deficient mice are completely resistant to lethal LPS doses and severely impaired in responses to viral and bacterial challenges, establishing IRAK-4 as an essential kinase in innate immunity. Gene targeting (knockout mice); in vivo LPS challenge; cytokine measurements in cultured cells Nature High 11923871
2014 Unphosphorylated IRAK4 dimerizes in solution (KD ~2.5 µM) via its kinase domain. Myddosome assembly greatly enhances IRAK4 kinase domain autophosphorylation at sub-KD concentrations. Crystal structure of the unphosphorylated IRAK4 kinase domain dimer captures a trans-autophosphorylation conformation where the activation loop phosphosite of one monomer is positioned for phosphotransfer by its partner. Dimerization is required for IRAK4 autophosphorylation in vitro and for ligand-dependent signaling in cells. Biophysical dimerization assays; X-ray crystallography of unphosphorylated kinase domain dimer; in vitro autophosphorylation assays; cell-based signaling assays with dimerization mutants Molecular cell High 25201411
2004 IRAK-4 is recruited to the IL-1R complex upon IL-1 stimulation and is required for the subsequent recruitment and activation/degradation of IRAK-1. Reconstitution of IRAK-4-deficient cells with wild-type vs. kinase-inactive IRAK-4 shows that kinase activity is required for optimal activation of IRAK-1, NF-κB, and JNK and maximal induction of inflammatory cytokines, but kinase-inactive IRAK-4 can still mediate some signals (scaffold function). Co-immunoprecipitation; reconstitution of IRAK-4-deficient cells with WT or kinase-inactive IRAK-4; NF-κB/JNK activation assays; cytokine induction assays The Journal of biological chemistry High 15292196
2007 IRAK4 kinase activity is critical for TLR-mediated innate immune responses: IRAK4 kinase-inactive knock-in mice are completely resistant to LPS- and CpG-induced shock. Kinase inactivity impairs TLR-mediated cytokine/chemokine induction in part by reducing LPS/R848/IL-1-mediated mRNA stability. TLR7- and TLR9-mediated type I interferon production in plasmacytoid dendritic cells is abolished in the absence of IRAK4 kinase activity. IRAK4 kinase-inactive knock-in mouse; in vivo LPS/CpG shock model; bone marrow-derived macrophage cytokine assays; pDC type I IFN measurement; mRNA stability assays The Journal of experimental medicine High 17470642
2018 IRAK4's scaffolding function (interaction with MyD88) is more critical for IL-1 signaling than its kinase activity. Kinase-inactive IRAK4 has stronger association with MyD88 and weaker association with IRAK1. Loss of MyD88 interaction (R12C compound variant) impairs IL-1-induced signaling more than loss of kinase activity (D329A variant). IRAK4 kinase activity modulates signal strength by controlling association of IRAK4, MyD88, and IRAK1. Co-immunoprecipitation of IRAK4 variants with MyD88/IRAK1; reconstitution of IRAK4-deficient cells; cytokine and NF-κB signaling quantitation; IRAK4 patient variant characterization The Journal of biological chemistry High 30115681
2022 The IRAK4 scaffold (not just its kinase activity) is required for activation of TRAF6 by both MyD88 and TRIF pathways downstream of TLR4. IRAK4 therefore integrates both MYD88-dependent and TRIF-dependent TLR4 signaling, an unexpected scaffold role beyond the MyD88 pathway. Genetic epistasis using IRAK4-deficient cells; kinase inhibitor dissecting kinase vs scaffold functions; measurement of TRAF6 activation and downstream signaling Cell reports Medium 35977521
2018 IRAK4 has a critical scaffold function in Myddosome formation that is independent of its kinase activity; selective IRAK4 kinase inhibition stabilizes Myddosome complexes while ablating TLR cytokine responses. IRAK4 kinase activity is dispensable for NF-κB and MAPK activation but essential for MyD88-dependent inflammatory cytokine production. Isolation of Myddosome complexes from primary mouse macrophages by co-immunoprecipitation; selective IRAK4 kinase inhibitor; kinetics of myddosome assembly/disassembly; cytokine and NF-κB/MAPK signaling assays The Journal of biological chemistry High 30076215
2004 IRAK4 kinase activity is redundant with IRAK1 kinase activity for IL-1-induced NF-κB, JNK activation, and IRAK phosphorylation in human IRAK4-deficient cells; kinase-inactive IRAK4 fully restores IL-1 signaling in these cells. Only combined inactivation of both IRAK and IRAK4 kinase activities efficiently abolishes the IL-1 pathway. IRAK4 is required for efficient recruitment of IRAK1 to the IL-1 receptor complex. Reconstitution of human IRAK4-deficient cells with WT or kinase-inactive IRAK4; NF-κB reporter assay; JNK activation; co-immunoprecipitation of IRAK1 with IL-1R complex The Journal of biological chemistry High 15084582
2002 Pellino 1 interacts with IRAK4, IRAK1, and TRAF6 in a signal-dependent complex required for NF-κB activation and IL-8 gene expression in response to IL-1. The Pellino 1-IRAK-IRAK4-TRAF6 complex is located between the IL-1 receptor complex and the TAK1 complex in the IL-1 pathway. Co-immunoprecipitation; NF-κB reporter assay; IL-8 gene expression measurement; dominant-negative/overexpression analysis The Journal of biological chemistry Medium 12496252
2003 Pellino2 is an interaction partner and substrate of IRAK4 (and IRAK1); Pellino2 interacts with both kinase-active and kinase-inactive forms of IRAK4 and IRAK1. Pellino2 acts as a scaffolding protein in TIR signaling but does not activate a specific transcription factor. Yeast two-hybrid; Co-immunoprecipitation; in vitro kinase assay showing Pellino2 phosphorylation by IRAK4; RNAi knockdown functional studies FEBS letters Medium 12860405
2010 IRAK1 and IRAK4 directly phosphorylate Mal (MyD88 adaptor-like/TIRAP), promoting its ubiquitination and proteasomal degradation. Kinase-inactive forms of either IRAK do not cause Mal depletion. LPS-induced Mal degradation is blocked by IRAK1/4 inhibitor or IRAK1/IRAK4 knockdown. MyD88 is not a substrate for either IRAK. This phosphorylation-driven Mal degradation negatively regulates TLR2 and TLR4 signaling. In vitro kinase assay (direct phosphorylation of Mal by IRAK1/IRAK4); co-expression with kinase-inactive mutants; ubiquitination assay; LPS stimulation with IRAK1/4 inhibitor and siRNA knockdown The Journal of biological chemistry High 20400509
2007 IRAK-4 phosphorylates p47phox (NADPH oxidase cytosolic factor) at serine and threonine residues (Thr133, Ser288, Thr356 identified by tandem MS), distinct from PKC phosphorylation sites. IRAK-4-phosphorylated p47phox activates the NADPH oxidase in a cell-free system. Endogenous IRAK-4 co-immunoprecipitates with p47phox and co-localizes at the plasma membrane after LPS stimulation. IRAK-4 overexpression increases NADPH oxidase activity in response to LPS. In vitro kinase assay; tandem mass spectrometry; cell-free NADPH oxidase activation assay; co-immunoprecipitation; immunofluorescence co-localization; IRAK-4 overexpression The Biochemical journal High 17217339
2017 IRAK4 is constitutively active as a kinase in resting cells; its intrinsic catalytic activity toward Pellino1 is not significantly increased by IL-1 stimulation. The IL-1-stimulated trans-autophosphorylation of IRAK4 is initiated by MyD88-induced dimerization rather than by an increase in intrinsic catalytic activity. In contrast, IRAK1 is inactive in unstimulated cells and activated by IL-1 or Pam3CSK4 through an allosteric mechanism dependent on its interaction with IRAK4, not by IRAK4-mediated phosphorylation. Pellino1 substrate-based kinase activity assays in human cell extracts; selective IRAK1 and IRAK4 pharmacological inhibitors; dephosphorylation/deubiquitylation experiments; IL-1R-expressing HEK293 cells, THP1 monocytes, primary macrophages The Biochemical journal Medium 28512203
2017 IRAK4 kinase activity controls TLR7/8-stimulated inflammatory cytokine production in human monocytes through activation of the transcription factor IRF5. IRAK4 inhibition abolishes IRF5 nuclear translocation and IRF5 binding to cytokine gene promoters. Mechanistically, IRAK4 kinase activity is required for IKKβ phosphorylation, which in turn activates IRF5; this pathway is distinct from canonical IKKβ-mediated IκB phosphorylation and NF-κB activation. Selective IRAK4 kinase inhibitor in primary human monocytes; transcriptomic analysis; biochemical IRF5 nuclear translocation assay; chromatin immunoprecipitation; IKKβ and TAK1 pharmacological inhibition The Journal of biological chemistry Medium 28924041
2019 U2AF1 mutations cause retention of exon 4 in IRAK4 mRNA, producing a longer isoform (IRAK4-L) that assembles with the Myddosome more efficiently and results in maximal NF-κB activation, driving oncogenic signaling in MDS and AML. Inhibition of IRAK4-L abrogates leukemic cell growth. Global exon usage analysis in AML samples; functional expression of IRAK4-L vs short isoform; NF-κB activation assays; leukemic cell growth inhibition; U2AF1 mutant cell models Nature cell biology High 31011167
2019 Crystal structures of unphosphorylated IRAK4 kinase domain in complex with ATP analog AMP-PNP (αC-out inactive conformation) and with type I inhibitors (DFG-in, αC-in active conformation) or type II inhibitors ponatinib/HG-12-6 (DFG-out conformation) reveal conformational flexibility of the unphosphorylated kinase. This flexibility allows unphosphorylated IRAK4 to adopt both active and inactive conformations depending on the bound ligand. X-ray crystallography of unphosphorylated IRAK4 kinase domain in multiple inhibitor-bound states (≤2.6 Å resolution); small-molecule screening for unphosphorylated IRAK4-selective inhibitors The Journal of biological chemistry High 30679311
2004 Prolonged stimulation of TLR2, TLR4, or TLR9 (but not TLR3) causes proteasome-dependent down-regulation of IRAK-4 protein and appearance of a 32-kDa C-terminal fragment, without affecting IRAK-4 mRNA levels. This down-regulation requires NF-κB activation and new protein synthesis and is blocked by proteasome inhibitors. Western blot analysis of IRAK-4 protein levels in RAW 264 macrophages after TLR stimulation; proteasome inhibitors; NF-κB inhibition; RT-PCR for mRNA levels Journal of leukocyte biology Medium 15258191
2011 Induction of endotoxin tolerance in vivo blocks TLR4-driven IRAK4 phosphorylation and activation in macrophages, while increasing expression of negative regulators IRAK-M, SHIP-1, and A20. Impaired IRAK4 activation correlates with reduced IκBα degradation, p38 phosphorylation, and cytokine expression. In vivo LPS tolerization mouse model; IRAK4 phosphorylation assay in peritoneal and splenic macrophages; RT-PCR for negative regulators; cytokine mRNA and protein measurements Journal of leukocyte biology Medium 21934070
2021 SARS-CoV-2-induced activation of human plasmacytoid dendritic cells (pDCs) and production of type I IFN, IL-6, and other cytokines critically depends on IRAK4 and UNC93B1, as established using pDCs from patients with genetic deficiencies in these proteins. Primary pDCs from IRAK4- and UNC93B1-deficient patients stimulated with live SARS-CoV-2 isolates; cytokine measurement; pDC subset diversification analysis The Journal of experimental medicine High 33533916
2016 In pericytes, MyD88 and its downstream kinase IRAK4 intrinsically control pericyte migration and conversion to myofibroblasts (fibrogenic differentiation), independent of their roles in classical immune cells. Pericyte-specific MyD88 ablation or pharmacological IRAK4 inhibition in vivo protects against kidney fibrosis. Pericyte-specific MyD88 conditional knockout; pharmacological IRAK4 inhibitor in kidney injury models; pericyte migration and myofibroblast differentiation assays The Journal of clinical investigation Medium 27869651
2010 Two human MyD88 death domain variants (S34Y and R98C) cause severely reduced NF-κB activation due to impaired MyD88 homo-oligomerization and reduced IRAK4 interaction. Structural modeling identifies Ser34 and Arg98 as residues important for Myddosome assembly. MyD88 homo-oligomerization and IRAK4 interaction are modulated by the MyD88 TIR domain and the IRAK4 kinase domain. Co-immunoprecipitation; NF-κB reporter assays; structural modeling of Myddosome assembly; receptor-specific signaling assays with MyD88 variants The Journal of biological chemistry Medium 20966070
2019 Acetylation of IRAK4 at K34 and phosphorylation at T345/S346 are post-translational modifications induced by LPS/D-Gal stimulation in vivo; oridonin attenuates these modifications and protects against acute liver injury. Western blot with modification-specific antibodies; RNA-seq and KEGG pathway analysis; in vivo ALI mouse model Mediators of inflammation Low 31611735
2009 IRAK4 kinase activity is required for IL-1-mediated induction of IL-23R expression, STAT3 activation by IL-23, and Th17 differentiation. Adoptive transfer of IRAK4 kinase-inactive Th17 cells fails to induce EAE, demonstrating a T-cell-intrinsic requirement for IRAK4 kinase activity in Th17-mediated autoimmunity. IRAK4 kinase-inactive knock-in mice; EAE model; adoptive transfer of Th17 cells; flow cytometry; cytokine assays; IL-23R expression analysis Journal of immunology Medium 19542468
2021 IRAK4 phosphorylates IRF5 and IRF4 in microglia (confirmed by Co-IP showing IRAK4 forms a Myddosome with MyD88/IRF5/IRF4); IRAK4 inhibition blocks IRF5/IRF4 nuclear translocation and quenches pro-inflammatory microglial responses to ischemia, improving neuronal viability. Co-immunoprecipitation of IRAK4/MyD88/IRF5/IRF4 complex; IRAK4 inhibitor (ND2158); nuclear translocation assay by immunofluorescence; ELISA for cytokines; oxygen-glucose deprivation model Cells Medium 33573200

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 883 20485341
2002 Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 628 11923871
2010 Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 319 21057262
2011 Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IκBα deficiency. Clinical microbiology reviews 294 21734245
2007 A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity. The Journal of experimental medicine 240 17470642
2019 U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies. Nature cell biology 205 31011167
2002 IRAK-4 as the central TIR signaling mediator in innate immunity. Trends in immunology 169 12297423
2007 Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound. Journal of leukocyte biology 156 17548806
2002 Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6) complex. The Journal of biological chemistry 148 12496252
2012 Regulation of TLR2-mediated tolerance and cross-tolerance through IRAK4 modulation by miR-132 and miR-212. Journal of immunology (Baltimore, Md. : 1950) 131 23264652
2021 SARS-CoV-2 induces human plasmacytoid predendritic cell diversification via UNC93B and IRAK4. The Journal of experimental medicine 123 33533916
2016 Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury. The Journal of clinical investigation 123 27869651
2014 IRAK4 dimerization and trans-autophosphorylation are induced by Myddosome assembly. Molecular cell 121 25201411
2009 IRAK-4 inhibitors for inflammation. Current topics in medicinal chemistry 120 19689377
2018 Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a dual role in myddosome formation and Toll-like receptor signaling. The Journal of biological chemistry 116 30076215
2004 The role of interleukin 1 receptor-associated kinase-4 (IRAK-4) kinase activity in IRAK-4-mediated signaling. The Journal of biological chemistry 113 15292196
2016 Cinnamaldehyde and allopurinol reduce fructose-induced cardiac inflammation and fibrosis by attenuating CD36-mediated TLR4/6-IRAK4/1 signaling to suppress NLRP3 inflammasome activation. Scientific reports 103 27270216
2019 Targeting IRAK4 for Degradation with PROTACs. ACS medicinal chemistry letters 101 31312412
2011 Induction of endotoxin tolerance in vivo inhibits activation of IRAK4 and increases negative regulators IRAK-M, SHIP-1, and A20. Journal of leukocyte biology 96 21934070
2023 IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial. Nature medicine 92 37957373
2004 IRAK4 kinase activity is redundant for interleukin-1 (IL-1) receptor-associated kinase phosphorylation and IL-1 responsiveness. The Journal of biological chemistry 89 15084582
2022 The IRAK4 scaffold integrates TLR4-driven TRIF and MYD88 signaling pathways. Cell reports 85 35977521
2014 Recent advances in the discovery of small molecule inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) as a therapeutic target for inflammation and oncology disorders. Journal of medicinal chemistry 85 25479567
2022 IRAK1 and IRAK4 as emerging therapeutic targets in hematologic malignancies. Current opinion in hematology 77 34743084
2017 The mechanism of activation of IRAK1 and IRAK4 by interleukin-1 and Toll-like receptor agonists. The Biochemical journal 73 28512203
2008 IRAK4 in TLR/IL-1R signaling: possible clinical applications. European journal of immunology 70 18286571
2017 IRAK4 kinase activity controls Toll-like receptor-induced inflammation through the transcription factor IRF5 in primary human monocytes. The Journal of biological chemistry 67 28924041
2016 Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity. Journal of immunology (Baltimore, Md. : 1950) 64 28003376
2016 MicroRNA-27a Negatively Modulates the Inflammatory Response in Lipopolysaccharide-Stimulated Microglia by Targeting TLR4 and IRAK4. Cellular and molecular neurobiology 61 26971344
2014 IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens. Blood 57 25320238
2007 Cross-talk between IRAK-4 and the NADPH oxidase. The Biochemical journal 57 17217339
2010 Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-myddosome assembly. The Journal of biological chemistry 55 20966070
2010 IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal). The Journal of biological chemistry 52 20400509
2024 Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases. Journal of medicinal chemistry 50 39151120
2022 IRAK4 Signaling Drives Resistance to Checkpoint Immunotherapy in Pancreatic Ductal Adenocarcinoma. Gastroenterology 49 35271824
2019 Interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors: an updated patent review (2016-2018). Expert opinion on therapeutic patents 49 30916602
2009 IRAK4 kinase activity is required for Th17 differentiation and Th17-mediated disease. Journal of immunology (Baltimore, Md. : 1950) 49 19542468
2020 Assessing IRAK4 Functions in ABC DLBCL by IRAK4 Kinase Inhibition and Protein Degradation. Cell chemical biology 47 32888499
2019 Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, in single and multiple ascending dose randomized phase 1 studies in healthy subjects. Arthritis research & therapy 46 31805989
2016 Suppression of IRAK1 or IRAK4 Catalytic Activity, but Not Type 1 IFN Signaling, Prevents Lupus Nephritis in Mice Expressing a Ubiquitin Binding-Defective Mutant of ABIN1. Journal of immunology (Baltimore, Md. : 1950) 46 27807192
2003 Characterization of Pellino2, a substrate of IRAK1 and IRAK4. FEBS letters 46 12860405
2020 Investigational IRAK-4 inhibitors for the treatment of rheumatoid arthritis. Expert opinion on investigational drugs 44 32255710
2017 Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265P Diffuse Large B-Cell Lymphoma. Journal of medicinal chemistry 42 29172502
2008 Genetic ablation of IRAK4 kinase activity inhibits vascular lesion formation. Biochemical and biophysical research communications 42 18190779
2020 IRAK4 inhibition: a promising strategy for treating RA joint inflammation and bone erosion. Cellular & molecular immunology 41 32415262
2019 Targeting IRAK4 disrupts inflammatory pathways and delays tumor development in chronic lymphocytic leukemia. Leukemia 40 31197259
2018 MicroRNA-302b negatively regulates IL-1β production in response to MSU crystals by targeting IRAK4 and EphA2. Arthritis research & therapy 40 29482609
2012 Complete dependence on IRAK4 kinase activity in TLR2, but not TLR4, signaling pathways underlies decreased cytokine production and increased susceptibility to Streptococcus pneumoniae infection in IRAK4 kinase-inactive mice. Journal of immunology (Baltimore, Md. : 1950) 40 23209321
2023 Tolerogenic dendritic cells and TLR4/IRAK4/NF-κB signaling pathway in allergic rhinitis. Frontiers in immunology 37 37915574
2019 IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer. JCI insight 37 31527315
2015 Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation. ACS medicinal chemistry letters 37 26101573
2023 IRAK4 inhibition dampens pathogenic processes driving inflammatory skin diseases. Science translational medicine 36 36791209
2020 Design, Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs. ACS medicinal chemistry letters 36 33488968
2008 IRAK-4 kinase activity is required for IRAK-4-dependent innate and adaptive immune responses. European journal of immunology 36 18286567
2004 Prolonged Toll-like receptor stimulation leads to down-regulation of IRAK-4 protein. Journal of leukocyte biology 36 15258191
2022 A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway. Acta pharmaceutica Sinica. B 35 36970199
2016 Association of polymorphisms in the MyD88, IRAK4 and TRAF6 genes and susceptibility to type 2 diabetes mellitus and diabetic nephropathy in a southern Han Chinese population. Molecular and cellular endocrinology 35 27062898
2009 Impaired priming and activation of the neutrophil NADPH oxidase in patients with IRAK4 or NEMO deficiency. Journal of immunology (Baltimore, Md. : 1950) 35 19414794
2018 Mechanism of dysfunction of human variants of the IRAK4 kinase and a role for its kinase activity in interleukin-1 receptor signaling. The Journal of biological chemistry 34 30115681
2008 IRAK-4 kinase activity-dependent and -independent regulation of lipopolysaccharide-inducible genes. European journal of immunology 33 18266302
2014 Structural dynamic analysis of apo and ATP-bound IRAK4 kinase. Scientific reports 32 25034608
2014 Identification of IRAK-4 in grouper (Epinephelus coioides) that impairs MyD88-dependent NF-κB activation. Developmental and comparative immunology 31 24631582
2013 Characterization of the interleukin 1 receptor-associated kinase 4 (IRAK4)-encoding gene in salmonid fish: the functional copy is rearranged in Oncorhynchus mykiss and that factor can impair TLR signaling in mammalian cells. Fish & shellfish immunology 31 24239597
2014 Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4. Bioorganic & medicinal chemistry letters 30 24726805
2014 Interleukin-1 receptor-associated kinase-4 (IRAK4) promotes inflammatory osteolysis by activating osteoclasts and inhibiting formation of foreign body giant cells. The Journal of biological chemistry 30 25404736
2007 Inherited human IRAK-4 deficiency: an update. Immunologic research 30 17917042
2020 The kinase IRAK4 promotes endosomal TLR and immune complex signaling in B cells and plasmacytoid dendritic cells. Science signaling 27 32487715
2013 Temozolomide-modulated glioma proteome: role of interleukin-1 receptor-associated kinase-4 (IRAK4) in chemosensitivity. Proteomics 27 23595970
2024 Discovery of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates Targeting MYD88 Mutant Diffuse Large B-Cell Lymphoma. Journal of medicinal chemistry 25 38920289
2015 3,3'-Diindolylmethane attenuates LPS-mediated acute liver failure by regulating miRNAs to target IRAK4 and suppress Toll-like receptor signalling. British journal of pharmacology 25 25521277
2013 Functional assessment of the mutational effects of human IRAK4 and MyD88 genes. Molecular immunology 25 24316379
2024 Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839. Journal of medicinal chemistry 24 38228402
2021 Phosphorylation of Microglial IRF5 and IRF4 by IRAK4 Regulates Inflammatory Responses to Ischemia. Cells 24 33573200
2020 Inhibition of IRAK4 kinase activity improves ethanol-induced liver injury in mice. Journal of hepatology 24 32682051
2016 Inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4): a patent review (2012-2015). Expert opinion on therapeutic patents 24 27310003
2019 Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors. Journal of medicinal chemistry 23 31082230
2023 IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies. Frontiers in immunology 22 37954584
2017 Small Molecule Inhibition of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4). Progress in medicinal chemistry 22 28314411
2020 IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation. Journal of clinical immunology 21 33083971
2017 Molecular characterization of Pacific oyster (Crassostrea gigas) IRAK4 gene and its role in MyD88-dependent pathway. Developmental and comparative immunology 21 28223161
2016 Cloning and functional characterization of IRAK4 in large yellow croaker (Larimichthys crocea) that associates with MyD88 but impairs NF-κB activation. Fish & shellfish immunology 21 27989863
2023 Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases. Clinical cancer research : an official journal of the American Association for Cancer Research 20 36749885
2022 Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macrophage inflammatory and glycolytic reprogramming. Cellular and molecular life sciences : CMLS 20 35588018
2018 Acanthoic acid suppresses lipin1/2 via TLR4 and IRAK4 signalling pathways in EtOH- and lipopolysaccharide-induced hepatic lipogenesis. The Journal of pharmacy and pharmacology 20 29341132
2024 Emerging interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors or degraders as therapeutic agents for autoimmune diseases and cancer. Acta pharmaceutica Sinica. B 19 39807338
2021 Pharmacological inhibition of IRAK1 and IRAK4 prevents endothelial inflammation and atherosclerosis in ApoE-/- mice. Pharmacological research 19 34954030
2019 Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor-associated kinase 4 (IRAK4). The Journal of biological chemistry 19 30679311
2014 Molecular cloning and expression of IRAK-4, IL-17 and I-κB genes in Haliotis rufescens challenged with Vibrio anguillarum. Fish & shellfish immunology 19 24398261
2022 Oral IRAK4 inhibitor BAY-1834845 prevents acute respiratory distress syndrome. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 18 36076574
2019 Molecular characterization, expression and functional analysis of IRAK1 and IRAK4 in Nile tilapia (Oreochromis niloticus). Fish & shellfish immunology 18 31846774
2017 Molecular cloning, structural modeling, and expression analysis of MyD88 and IRAK4 of golden pompano (Trachinotus ovatus). Developmental and comparative immunology 18 28408332
2013 IRAK4 kinase activity is not required for induction of endotoxin tolerance but contributes to TLR2-mediated tolerance. Journal of leukocyte biology 18 23695305
2012 Identification and characterization of IL-1 receptor-associated kinase-4 (IRAK-4) in half-smooth tongue sole Cynoglossus semilaevis. Fish & shellfish immunology 18 22230843
2019 Protective Effects of Oridonin on Acute Liver Injury via Impeding Posttranslational Modifications of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) in the Toll-Like Receptor 4 (TLR4) Signaling Pathway. Mediators of inflammation 17 31611735
2021 Tumor cell intrinsic RON signaling suppresses innate immune responses in breast cancer through inhibition of IRAK4 signaling. Cancer letters 16 33508385
2020 Design and synthesis of Imidazo[1,2-b]pyridazine IRAK4 inhibitors for the treatment of mutant MYD88 L265P diffuse large B-cell lymphoma. European journal of medicinal chemistry 16 32014679
2017 Deficiency in IRAK4 activity attenuates manifestations of murine Lupus. European journal of immunology 16 28295231
2015 Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors. ACS medicinal chemistry letters 16 26288698
2019 Identification and functional characterization of IRAK-4 in grass carp (Ctenopharyngodon idellus). Fish & shellfish immunology 15 30685465
2017 Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation. Bioorganic & medicinal chemistry letters 15 28501511

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