Affinage

IRAK4

Interleukin-1 receptor-associated kinase 4 · UniProt Q9NWZ3

Length
460 aa
Mass
51.5 kDa
Annotated
2026-04-28
100 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IRAK4 is a serine/threonine kinase essential for innate and adaptive immunity, functioning as the apical kinase in TLR and IL-1R signaling pathways. Upon receptor stimulation, IRAK4 is recruited via its N-terminal death domain into the Myddosome, a left-handed helical oligomeric complex with MyD88 and IRAK1/2, where it undergoes cis-autophosphorylation of activation-loop residues T342, T345, and S346 to achieve full catalytic activity and then phosphorylates IRAK1 to propagate signals through TRAF6 to NF-κB and MAPK cascades (PMID:20485341, PMID:11960013, PMID:17141195). Beyond IRAK1, IRAK4 directly phosphorylates p47phox to activate NADPH oxidase, Pellino E3 ubiquitin ligases to promote their ligase activity, the adaptor Mal to trigger its proteasomal degradation as a negative feedback mechanism, and the transcription factors IRF5 and IRF4 to drive inflammatory gene expression and type I interferon production (PMID:17217339, PMID:19264966, PMID:20400509, PMID:28924041). IRAK4 also possesses a kinase-independent scaffolding function required for TRIF-dependent TRAF6 activation downstream of TLR4, and an oncogenic long isoform (IRAK4-L, retaining exon 4) generated by U2AF1 spliceosome mutations drives constitutive NF-κB activation in MDS and AML (PMID:35977521, PMID:31011167).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2002 High

    IRAK4 was identified as the kinase upstream of IRAK1 in IL-1R/TLR signaling, resolving the question of what kinase initiates signal propagation from receptor complexes to NF-κB and MAPK pathways.

    Evidence Co-IP, dominant-negative constructs, in vitro kinase assays, and NF-κB reporters in mammalian cells; corroborated by IRAK4-knockout mice showing complete abrogation of IL-1/TLR responses and resistance to LPS shock

    PMID:11923871 PMID:11960013

    Open questions at the time
    • Direct structural basis for IRAK4 recruitment to receptor complexes unknown
    • Whether IRAK4 has kinase-independent signaling roles not addressed
  2. 2004 High

    Reconstitution of IRAK4-deficient cells with kinase-inactive IRAK4 revealed that IRAK4 possesses both kinase-dependent and kinase-independent signaling functions, establishing that catalytic activity is required for maximal but not all downstream outputs.

    Evidence Reconstitution of IRAK4-deficient cells with WT vs. kinase-dead IRAK4, reporter and cytokine assays

    PMID:15292196

    Open questions at the time
    • Which downstream pathways are scaffold-dependent vs. kinase-dependent not delineated
    • Mechanism of IRAK4 degradation as negative feedback only partially characterized
  3. 2006 High

    Identification of activation-loop autophosphorylation sites (T342, T345, S346) and demonstration of cis-autophosphorylation resolved how IRAK4 achieves catalytic competence without a separate upstream kinase.

    Evidence LC-MS/MS phosphosite mapping, site-directed mutagenesis, in vitro kinase assays including trans-phosphorylation controls

    PMID:17141195

    Open questions at the time
    • Whether autophosphorylation occurs before or after Myddosome assembly in cells not determined
    • Structural basis for cis vs. trans selectivity unknown
  4. 2007 High

    IRAK4 kinase-inactive knock-in mice established that kinase activity is essential for LPS-induced shock, TLR-dependent mRNA stability, and type I interferon production by pDCs, while NF-κB activation is only partially kinase-dependent — genetically separating kinase from scaffold functions in vivo.

    Evidence IRAK4 kinase-inactive knock-in mouse with cytokine, IFN, and mRNA stability measurements

    PMID:17470642

    Open questions at the time
    • Molecular basis for kinase-independent NF-κB activation not identified
  5. 2007 High

    Discovery that IRAK4 directly phosphorylates p47phox to activate NADPH oxidase expanded the substrate repertoire beyond the IRAK family, linking TLR signaling to reactive oxygen species production.

    Evidence In vitro kinase assay with MS phosphosite mapping, co-IP, cell-free NADPH oxidase reconstitution

    PMID:17217339

    Open questions at the time
    • In vivo relevance of IRAK4-p47phox axis in infectious or inflammatory contexts not tested
  6. 2009 High

    Structural and biophysical characterization of the MyD88–IRAK4 death domain complex revealed an oligomeric assembly (Myddosome) with defined stoichiometries, culminating in a crystal structure of the MyD88–IRAK4–IRAK2 ternary complex as a left-handed helical oligomer with hierarchical assembly.

    Evidence Native mass spectrometry, SAXS, and X-ray crystallography with mutagenesis validation

    PMID:19592493 PMID:20485341

    Open questions at the time
    • How Myddosome assembly is regulated at endogenous protein concentrations unclear
    • Full-length IRAK4 structure within the complex not resolved
  7. 2009 High

    Demonstration that IRAK4 (and IRAK1) phosphorylate Pellino E3 ligases at multiple sites to activate ubiquitin ligase activity established a direct enzymatic link between IRAK kinases and ubiquitin-dependent signal amplification.

    Evidence In vitro kinase assay, mutagenesis of seven phosphosites, reconstituted E3 ligase activity assays

    PMID:19264966

    Open questions at the time
    • Relative contributions of IRAK4 vs. IRAK1 to Pellino phosphorylation in vivo not resolved
  8. 2010 High

    IRAK4 (with IRAK1) phosphorylates the adaptor Mal to trigger its ubiquitination and proteasomal degradation, establishing a kinase-dependent negative feedback loop that terminates TLR2/4 signaling.

    Evidence In vitro kinase assay, ubiquitination assays, siRNA knockdown, pharmacological IRAK1/4 inhibition

    PMID:20400509

    Open questions at the time
    • Specific phosphosites on Mal targeted by IRAK4 not mapped
    • Whether Mal degradation limits all TLR responses or is pathway-selective unknown
  9. 2017 Medium

    Pharmacological IRAK4 inhibition in human monocytes showed that IRAK4 kinase activity controls IRF5 nuclear translocation and promoter binding through a TAK1–IKKβ–IRF5 axis, identifying the mechanistic link between IRAK4 and transcription factor-driven inflammatory gene programs.

    Evidence Selective IRAK4 inhibitor, nuclear fractionation, ChIP, transcriptomics in primary human monocytes

    PMID:28924041

    Open questions at the time
    • Whether IRAK4 directly phosphorylates IRF5 or acts exclusively through IKKβ not fully resolved in this system
    • Inhibitor selectivity profile could confound interpretation
  10. 2019 High

    An oncogenic IRAK4 long isoform (IRAK4-L, retaining exon 4) driven by U2AF1 spliceosome mutations was shown to be essential for Myddosome assembly and NF-κB hyperactivation in MDS/AML, linking IRAK4 splice regulation to leukemogenesis.

    Evidence Exon usage analysis, isoform-specific expression, Myddosome assembly assays, NF-κB reporter, loss-of-function in leukemic cells

    PMID:31011167

    Open questions at the time
    • Whether IRAK4-L has distinct substrate specificity vs. IRAK4-S not determined
    • Therapeutic window for IRAK4 inhibition in these malignancies requires clinical data
  11. 2022 High

    Genetic epistasis definitively separated IRAK4 scaffold from kinase functions at TLR4: the scaffold is required for TRAF6 activation by both MYD88 and TRIF pathways, while kinase activity is selectively essential for MYD88-dependent signaling.

    Evidence Reconstitution of IRAK4-deficient cells with WT vs. kinase-inactive IRAK4, TRAF6 ubiquitination assays

    PMID:35977521

    Open questions at the time
    • Structural mechanism by which IRAK4 scaffold enables TRIF-TRAF6 activation unknown
    • Whether IRAK4 scaffold function is relevant at other TLRs beyond TLR4 not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of full-length IRAK4 within the Myddosome, how IRAK4 scaffold function integrates TRIF-dependent signaling, the full in vivo substrate landscape, and the therapeutic index of IRAK4 kinase inhibitors vs. degraders in autoimmune and oncologic settings.
  • Full-length IRAK4 structure in complex not available
  • Complete in vivo phosphoproteomics of IRAK4 substrates lacking
  • Relative therapeutic benefit of kinase inhibition vs. protein degradation not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0060090 molecular adaptor activity 2
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 6 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1643685 Disease 1
Partners
IRAK1IRAK2IRF5MYD88NCF1PELI1TIRAPTRAF6
Complex memberships
Myddosome

Evidence

Reading pass · 24 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) consisting of 6 MyD88, 4 IRAK4, and 4 IRAK2 death domains. Assembly is hierarchical: MyD88 recruits IRAK4, and the MyD88-IRAK4 sub-complex recruits IRAK2 or IRAK1. Composite binding sites confirmed by mutagenesis; proximity of IRAK kinase domains enables trans-phosphorylation and activation. X-ray crystallography of death domain complex, mutagenesis validation Nature High 20485341
2009 The death domains of human MyD88 and IRAK4 assemble into closed oligomeric complexes (Myddosome) with unusual stoichiometries of 7:4 and 8:4 (MyD88:IRAK4), as determined by native mass spectrometry and solution scattering. TLR4 pathway activation requires receptor clustering into lipid rafts. Native mass spectrometry, small-angle X-ray scattering, lipid raft fractionation The Journal of biological chemistry High 19592493
2002 IRAK4 is identified as a novel IRAK family member; endogenous IRAK4 interacts with IRAK1 and TRAF6 in an IL-1-dependent manner. IRAK4 overexpression activates NF-κB and MAP kinase pathways, and IRAK4 phosphorylates IRAK1. Dominant-negative IRAK4 blocks IL-1-induced IRAK1 activation and modification, placing IRAK4 upstream of IRAK1. Kinase activity is required for NF-κB activation. Co-immunoprecipitation, overexpression/dominant-negative constructs, in vitro kinase assay, NF-κB reporter assay Proceedings of the National Academy of Sciences of the United States of America High 11960013
2002 Gene targeting of IRAK4 in mice shows it is indispensable for IL-1R and TLR signaling. IRAK4-deficient animals are completely resistant to LPS-induced lethal shock and severely impaired in responses to viral and bacterial challenges, establishing IRAK4 as essential for innate immunity. Gene targeting (knockout mouse), LPS challenge, cytokine measurements Nature High 11923871
2004 IRAK4 is recruited to the IL-1R complex upon IL-1 stimulation and is required for recruitment and subsequent activation/degradation of IRAK1. Kinase activity of IRAK4 is required for optimal IL-1-induced IRAK1 activation, NF-κB, and JNK signaling and maximal cytokine induction; however, kinase-inactive IRAK4 can still mediate some signals, indicating both kinase-dependent and -independent signaling. Reconstitution of IRAK4-deficient cells with WT or kinase-inactive IRAK4, co-immunoprecipitation, reporter assays The Journal of biological chemistry High 15292196
2006 IRAK4 kinase activity is regulated by autophosphorylation within its activation loop at residues T342, T345, and S346. Site-directed mutagenesis of these residues significantly reduces catalytic activity. Autophosphorylation is intramolecular (cis), as wild-type IRAK4 fails to trans-phosphorylate kinase-inactive IRAK4. LC-MS/MS phosphosite identification, site-directed mutagenesis, in vitro kinase assay, trans-phosphorylation experiment Biochemical and biophysical research communications High 17141195
2007 IRAK4 kinase-inactive knock-in mice are completely resistant to LPS- and CpG-induced shock; TLR/IL-1R-mediated NF-κB activation is partially preserved but LPS-induced mRNA stability of cytokines is reduced. TLR7- and TLR9-mediated type I interferon production in plasmacytoid dendritic cells requires IRAK4 kinase activity. IRAK4 kinase-inactive knock-in mouse, cytokine/IFN measurements, mRNA stability assay The Journal of experimental medicine High 17470642
2007 IRAK4 phosphorylates the NADPH oxidase cytosolic component p47phox at both serine and threonine residues (Thr133, Ser288, Thr356 identified by MS), activating NADPH oxidase in a cell-free system. Endogenous IRAK4 interacts with p47phox and co-localizes at the plasma membrane after LPS stimulation. IRAK4 overexpression increases NADPH oxidase activity in response to LPS. In vitro kinase assay, tandem MS phosphosite mapping, co-immunoprecipitation, immunofluorescence, cell-free NADPH oxidase reconstitution The Biochemical journal High 17217339
2009 IRAK1 and IRAK4 directly phosphorylate the E3 ubiquitin ligase Pellino, with seven phosphorylation sites (Ser76, Ser78, Thr80, Ser82, Thr86, Thr288, Ser293) critical for activation of Pellino1's E3 ligase activity. Full activation can be achieved by phosphorylating any one of several different sites, providing a mechanism for prolonged Pellino activity. In vitro kinase assay, site-directed mutagenesis, E3 ubiquitin ligase assay with multiple E2 enzymes Proceedings of the National Academy of Sciences of the United States of America High 19264966
2003 Pellino2 is identified as an interaction partner and substrate of IRAK4 (and IRAK1). Pellino2 interacts with both kinase-active and kinase-inactive IRAK4, and functional studies suggest a scaffolding role linking TIR signaling to basic cellular processes. Co-immunoprecipitation, in vitro kinase assay, RNAi knockdown, overexpression FEBS letters Medium 12860405
2010 IRAK1 and IRAK4 directly phosphorylate the TLR2/4 adaptor Mal (MyD88 adaptor-like), promoting its ubiquitination and proteasomal degradation. Kinase-inactive forms of either IRAK do not cause Mal depletion, and LPS-induced Mal ubiquitination is blocked by IRAK1/4 inhibitor or dual knockdown, providing a negative feedback mechanism for TLR2 and TLR4 signaling. In vitro kinase assay, co-expression, ubiquitination assay, siRNA knockdown, pharmacological inhibition The Journal of biological chemistry High 20400509
2010 MyD88 variants S34Y and R98C in the death domain severely reduce NF-κB activation due to impaired MyD88 homo-oligomerization and IRAK4 interaction, confirming that MyD88 homo-oligomerization and IRAK4 recruitment are essential for Myddosome assembly and downstream signaling. Co-immunoprecipitation, NF-κB reporter assay, structural modeling, functional cell-based assays The Journal of biological chemistry Medium 20966070
2017 IRAK4 kinase activity controls TLR-induced inflammatory cytokine production in human monocytes through activation of the transcription factor IRF5. Pharmacological IRAK4 inhibition abolishes IRF5 nuclear translocation and promoter binding after TLR7/8 stimulation, and blocks IKKβ phosphorylation upstream of IRF5 (but not NFκB nuclear translocation), via a TAK1-IKKβ-IRF5 axis. Transcriptomics, biochemical assays, selective IRAK4 inhibitor, nuclear fractionation, ChIP The Journal of biological chemistry Medium 28924041
2019 IRAK4 kinase activity controls Th17 differentiation: kinase-inactive IRAK4 knock-in mice are resistant to experimental autoimmune encephalomyelitis, with defects in IRAK4-dependent IL-23R expression, STAT3 activation by IL-23, and Th17 cytokine production. IL-1-mediated IRAK4 kinase activity in T cells is required for IL-23R induction and Th17 differentiation. IRAK4 kinase-inactive knock-in mouse, adoptive transfer of Th17 cells, STAT3 signaling assays, cytokine measurements Journal of immunology High 19542468
2022 The IRAK4 scaffold (kinase-independent function) is required for activation of TRAF6 by both MYD88 and TRIF downstream of TLR4, integrating both signaling arms. IRAK4 kinase activity is essential for MYD88 signaling specifically. Genetic epistasis using IRAK4-deficient cells, reconstitution with WT vs. kinase-inactive IRAK4, TRAF6 ubiquitination assays Cell reports High 35977521
2019 Dimethyl fumarate (DMF) covalently modifies Cys13 of IRAK4, blocking IRAK4-MyD88 interactions and IRAK4-mediated cytokine production in a Cys13-dependent manner, identifying the IRAK4-MyD88 protein-protein interface as a druggable target. Chemical proteomics (activity-based protein profiling), mutagenesis (Cys13 mutant), co-immunoprecipitation, cytokine assays Journal of immunology High 30885957
2004 Prolonged stimulation of TLR2, TLR4, or TLR9 (but not TLR3) causes proteasome-dependent down-regulation of IRAK4 protein and appearance of a 32-kDa C-terminal fragment, mediated through a protease induced by NF-κB activation, suggesting a negative feedback mechanism. Western blot, proteasome inhibitors, NF-κB inhibitors, macrophage cell line Journal of leukocyte biology Medium 15258191
2019 U2AF1 spliceosome mutations mediate expression of an oncogenic IRAK4 long isoform (IRAK4-L, retaining exon 4) in MDS and AML. IRAK4-L assembles with the Myddosome and results in maximal NF-κB activation and is essential for leukemic cell function; inhibition of IRAK4-L abrogates leukemic growth. Exon usage analysis, isoform-specific expression, myddosome assembly assay, NF-κB reporter, loss-of-function Nature cell biology High 31011167
2021 SARS-CoV-2-induced plasmacytoid dendritic cell (pDC) activation critically depends on IRAK4 and UNC93B1, as established using pDCs from genetically deficient patients. All major aspects of pDC activation (IFN-α, IL-6, IP-10 production, and pDC diversification) were abrogated in IRAK4-deficient pDCs. Primary pDCs from IRAK4-deficient patients, cytokine measurements, viral stimulation The Journal of experimental medicine High 33533916
2016 MyD88 and IRAK4 intrinsically control pericyte migration and conversion to myofibroblasts independent of their inflammatory roles. Specific ablation of MyD88 in pericytes or pharmacological IRAK4 inhibition in vivo protects against kidney injury by attenuating myofibroblast differentiation. Pericyte-specific MyD88 knockout, pharmacological IRAK4 inhibitor in vivo, kidney injury model, migration assays The Journal of clinical investigation Medium 27869651
2021 IRAK4 phosphorylates IRF5 and IRF4 in microglia, which subsequently translocate to the nucleus. IRAK4 forms a Myddosome complex with MyD88/IRF5/IRF4. IRAK4 inhibition quenches microglial pro-inflammatory responses and increases neuronal viability after ischemia. Co-immunoprecipitation, Western blot, immunofluorescence, IRAK4 inhibitor, oxygen-glucose deprivation model Cells Medium 33573200
2008 IRAK4 kinase activity is required for in vivo and in vitro cytokine production in response to TLR ligands and adaptive immune responses to viral infection. T cell responses to LCMV infection are impaired in IRAK4-knockout and kinase-dead knock-in mice, establishing an IRAK4 kinase-dependent role in adaptive immunity. IRAK4 kinase-dead knock-in mouse, LCMV infection, cytokine measurement, T cell proliferation assay European journal of immunology High 18286567
2013 IRAK4 protein levels in glioma cells correlate with temozolomide sensitivity. RNAi-mediated knockdown of IRAK4 renders glioma cells resistant to temozolomide, and TMZ-induced upregulation of IRAK4 leads to IRAK1 downregulation and inhibition of the NF-κB pathway. 2D-DIGE proteomics, RNAi knockdown, Western blot, cell viability assay Proteomics Low 23595970
2011 In vivo endotoxin tolerance blocks TLR4-driven IRAK4 phosphorylation and activation in macrophages, while increasing expression of negative regulators IRAK-M, SHIP-1, and A20, demonstrating that IRAK4 activation status is a regulated checkpoint in endotoxin tolerance. In vivo LPS tolerization model, IRAK4 phosphorylation assay, gene expression analysis Journal of leukocyte biology Medium 21934070

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 878 20485341
2002 Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 627 11923871
2002 IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proceedings of the National Academy of Sciences of the United States of America 522 11960013
2010 Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 315 21057262
2009 An oligomeric signaling platform formed by the Toll-like receptor signal transducers MyD88 and IRAK-4. The Journal of biological chemistry 311 19592493
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
2005 Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses. Immunity 224 16286015
2019 U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies. Nature cell biology 201 31011167
2005 Functional characterization of full-length TLR3, IRAK-4, and TRAF6 in zebrafish (Danio rerio). Molecular immunology 185 15829296
2008 IRAK-4- and MyD88-dependent pathways are essential for the removal of developing autoreactive B cells in humans. Immunity 184 19006693
2007 Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound. Journal of leukocyte biology 153 17548806
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
2009 IRAK-4 inhibitors for inflammation. Current topics in medicinal chemistry 119 19689377
2017 Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design. Journal of medicinal chemistry 116 28498658
2004 The role of interleukin 1 receptor-associated kinase-4 (IRAK-4) kinase activity in IRAK-4-mediated signaling. The Journal of biological chemistry 112 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
2015 The dietary flavonoid Kaempferol mediates anti-inflammatory responses via the Src, Syk, IRAK1, and IRAK4 molecular targets. Mediators of inflammation 92 25922567
2014 MicroRNA-302b augments host defense to bacteria by regulating inflammatory responses via feedback to TLR/IRAK4 circuits. Nature communications 91 24717937
2023 IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial. Nature medicine 86 37957373
2022 The IRAK4 scaffold integrates TLR4-driven TRIF and MYD88 signaling pathways. Cell reports 80 35977521
2022 IRAK1 and IRAK4 as emerging therapeutic targets in hematologic malignancies. Current opinion in hematology 72 34743084
2009 Identification of the phosphorylation sites on the E3 ubiquitin ligase Pellino that are critical for activation by IRAK1 and IRAK4. Proceedings of the National Academy of Sciences of the United States of America 67 19264966
2017 IRAK4 kinase activity controls Toll-like receptor-induced inflammation through the transcription factor IRF5 in primary human monocytes. The Journal of biological chemistry 66 28924041
2015 MicroRNA367 negatively regulates the inflammatory response of microglia by targeting IRAK4 in intracerebral hemorrhage. Journal of neuroinflammation 66 26552593
2016 Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity. Journal of immunology (Baltimore, Md. : 1950) 63 28003376
2016 MicroRNA-27a Negatively Modulates the Inflammatory Response in Lipopolysaccharide-Stimulated Microglia by Targeting TLR4 and IRAK4. Cellular and molecular neurobiology 61 26971344
2006 Regulation of IRAK-4 kinase activity via autophosphorylation within its activation loop. Biochemical and biophysical research communications 59 17141195
2007 Cross-talk between IRAK-4 and the NADPH oxidase. The Biochemical journal 57 17217339
2014 IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens. Blood 55 25320238
2010 Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-myddosome assembly. The Journal of biological chemistry 55 20966070
2020 Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies. ACS medicinal chemistry letters 52 33335659
2010 IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal). The Journal of biological chemistry 52 20400509
2014 MicroRNA-93 inhibits inflammatory cytokine production in LPS-stimulated murine macrophages by targeting IRAK4. FEBS letters 51 24642374
2022 IRAK4 Signaling Drives Resistance to Checkpoint Immunotherapy in Pancreatic Ductal Adenocarcinoma. Gastroenterology 49 35271824
2019 Dimethyl Fumarate Disrupts Human Innate Immune Signaling by Targeting the IRAK4-MyD88 Complex. Journal of immunology (Baltimore, Md. : 1950) 49 30885957
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
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
2014 IRAK4 as a molecular target in the amelioration of innate immunity-related endotoxic shock and acute liver injury by chlorogenic acid. Journal of immunology (Baltimore, Md. : 1950) 46 25548221
2003 Characterization of Pellino2, a substrate of IRAK1 and IRAK4. FEBS letters 46 12860405
2024 Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases. Journal of medicinal chemistry 43 39151120
2021 Long noncoding RNA IRL regulates NF-κB-mediated immune responses through suppression of miR-27c-3p-dependent IRAK4 downregulation in teleost fish. The Journal of biological chemistry 43 33465375
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 Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor. Arthritis research & therapy 40 30355354
2018 MicroRNA-302b negatively regulates IL-1β production in response to MSU crystals by targeting IRAK4 and EphA2. Arthritis research & therapy 39 29482609
2015 Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation. ACS medicinal chemistry letters 37 26101573
2020 Design, Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs. ACS medicinal chemistry letters 36 33488968
2019 IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer. JCI insight 36 31527315
2008 IRAK-4 kinase activity is required for IRAK-4-dependent innate and adaptive immune responses. European journal of immunology 36 18286567
2006 IRAK-4 mutation (Q293X): rapid detection and characterization of defective post-transcriptional TLR/IL-1R responses in human myeloid and non-myeloid cells. Journal of immunology (Baltimore, Md. : 1950) 36 17114497
2004 Prolonged Toll-like receptor stimulation leads to down-regulation of IRAK-4 protein. Journal of leukocyte biology 36 15258191
2023 IRAK4 inhibition dampens pathogenic processes driving inflammatory skin diseases. Science translational medicine 35 36791209
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
2023 Tolerogenic dendritic cells and TLR4/IRAK4/NF-κB signaling pathway in allergic rhinitis. Frontiers in immunology 34 37915574
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 34 36970199
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
2008 Down-regulation of IRAK-4 is a component of LPS- and CpG DNA-induced tolerance in macrophages. Cellular signalling 31 18992325
2014 Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4. Bioorganic & medicinal chemistry letters 30 24726805
2015 Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4. ACS medicinal chemistry letters 28 26101574
2013 Temozolomide-modulated glioma proteome: role of interleukin-1 receptor-associated kinase-4 (IRAK4) in chemosensitivity. Proteomics 27 23595970
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
2016 Inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4): a patent review (2012-2015). Expert opinion on therapeutic patents 24 27310003
2024 Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839. Journal of medicinal chemistry 23 38228402
2021 Phosphorylation of Microglial IRF5 and IRF4 by IRAK4 Regulates Inflammatory Responses to Ischemia. Cells 23 33573200
2020 Inhibition of IRAK4 kinase activity improves ethanol-induced liver injury in mice. Journal of hepatology 23 32682051
2019 Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors. Journal of medicinal chemistry 23 31082230
2017 Small Molecule Inhibition of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4). Progress in medicinal chemistry 22 28314411
2015 Brazilein Suppresses Inflammation through Inactivation of IRAK4-NF-κB Pathway in LPS-Induced Raw264.7 Macrophage Cells. International journal of molecular sciences 22 26593910
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
2020 IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation. Journal of clinical immunology 20 33083971
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
2023 IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies. Frontiers in immunology 19 37954584
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
2014 A novel benzenediamine derivate rescued mice from experimental sepsis by attenuating proinflammatory mediators via IRAK4. American journal of respiratory cell and molecular biology 19 24588661
2021 Pharmacological inhibition of IRAK1 and IRAK4 prevents endothelial inflammation and atherosclerosis in ApoE-/- mice. Pharmacological research 18 34954030
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
2012 Effect of taurine on IRAK4 and NF-kappa B in Kupffer cells from rat liver grafts after ischemia-reperfusion injury. American journal of surgery 18 22771449
2019 Discovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity. ACS medicinal chemistry letters 17 32184965
2018 Optimization of permeability in a series of pyrrolotriazine inhibitors of IRAK4. Bioorganic & medicinal chemistry 17 29398441
2024 Emerging interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors or degraders as therapeutic agents for autoimmune diseases and cancer. Acta pharmaceutica Sinica. B 16 39807338
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
2015 Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors. ACS medicinal chemistry letters 16 26288698
2011 A nonsynonymous polymorphism of IRAK4 associated with increased prevalence of gram-positive infection and decreased response to toll-like receptor ligands. Journal of innate immunity 16 21576904
2019 Discovery of a Series of 5-Azaquinazolines as Orally Efficacious IRAK4 Inhibitors Targeting MyD88L265P Mutant Diffuse Large B Cell Lymphoma. Journal of medicinal chemistry 15 31622099
2017 Deficiency in IRAK4 activity attenuates manifestations of murine Lupus. European journal of immunology 15 28295231
2017 Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation. Bioorganic & medicinal chemistry letters 15 28501511
2016 Efforts towards the optimization of a bi-aryl class of potent IRAK4 inhibitors. Bioorganic & medicinal chemistry letters 14 27476420