Affinage

Showing IRAK1 — IRAK is a alias.

IRAK1

Interleukin-1 receptor-associated kinase 1 · UniProt P51617

Length
712 aa
Mass
76.5 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 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

IRAK1 is a serine/threonine protein kinase that serves as a proximal signal transducer of the IL-1 receptor and Toll-like receptor family, coupling receptor engagement to NF-κB activation (PMID:8599092, PMID:9374458). Its core signaling logic is conserved from the Drosophila ortholog Pelle, which acts downstream of Tube in the Toll dorsoventral patterning pathway: Pelle is recruited to the membrane through a death-domain heterodimer with Tube and, once oligomerized, drives nuclear import of the NF-κB-like factor Dorsal (PMID:7527496, PMID:7635064, PMID:10589682, PMID:10330490). In the mammalian pathway IRAK1 assembles with MyD88 and IRAK-2 at the receptor (PMID:9374458) and is recruited and activated by upstream IRAK4, whose kinase activity phosphorylates IRAK1 and is required for optimal IRAK1 activation (PMID:11960013, PMID:15292196); structurally, the IRAK1 kinase domain remains monomeric and is licensed by forming a heterodimer with phosphorylated IRAK4, defining a two-step Myddosome activation mechanism that operates allosterically rather than through a single covalent mark (PMID:29208712, PMID:28512203). Activated IRAK1 feeds into NF-κB, MAPK/JNK, and the TAK1/TAB1 module, and acts as a signaling branchpoint in which the death domain and N-proximal region, not kinase activity, are needed for some outputs (PMID:11745395); IRAK1 also enables priming-independent NLRP3 inflammasome assembly and rapid caspase-1 activation in a kinase-dependent manner (PMID:24379360). Beyond cytoplasmic signaling, IRAK1 translocates to the nucleus, binds NF-κB target promoters, and phosphorylates histone H3 at serine 10 to enhance transcriptional output (PMID:18276832). IRAK1 directly phosphorylates substrates including the adaptor Mal, targeting it for ubiquitin-dependent degradation (PMID:20400509). Its activity is tuned by multiple negative regulators—IRAK-M blocks IRAK1 dissociation from MyD88 and formation of IRAK1-TRAF6 complexes (PMID:12150927), the deubiquitinase A20 reverses K63-linked IRAK1 ubiquitination during endotoxin tolerance (PMID:21220427), and the glucocorticoid receptor interferes with β-TrCP-mediated K48 ubiquitination required for IRAK1 trafficking (PMID:29038250). IRAK1 additionally functions in malignancy and stress responses, promoting radioresistance through PIN1-dependent activation and PRDX1 stabilization, stabilizing the anti-apoptotic protein MCL1 via TRAF6/K63-ubiquitination, and sustaining leukemic stem/progenitor states, in part through scaffolding rather than catalytic functions (PMID:30664786, PMID:25642772, PMID:37031183, PMID:34279092, PMID:37172199).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1993 High

    Established that the IRAK1 ortholog is a catalytically essential kinase whose function is to relay a receptor signal to nuclear transcription factor activation, defining the gene as an essential transducer rather than a structural component.

    Evidence Cloning and active-site mutagenesis of Drosophila Pelle with in vivo Dorsal nuclear-import readout

    PMID:8440018

    Open questions at the time
    • Mammalian substrates not yet identified
    • Mechanism of kinase activation undefined
  2. 1995 High

    Showed that the kinase is positioned at the membrane through an upstream death-domain adaptor, answering how the cytoplasmic kinase is recruited to an activated receptor.

    Evidence Yeast two-hybrid, immunolocalization, and membrane-targeted fusion rescue of Pelle-Tube interaction in Drosophila embryos

    PMID:7635064

    Open questions at the time
    • Stoichiometry and dynamics of recruitment not resolved
    • Connection to receptor occupancy quantitative only later
  3. 1996 High

    Identified mammalian IRAK1 biochemically and placed it physically at the IL-1 receptor, connecting IL-1R engagement to NF-κB activation in human cells.

    Evidence Protein purification, cDNA cloning, and Co-IP with IL-1RI plus phosphorylation assay in HEK293/HeLa; parallel mouse mPLK in vitro kinase assay on IκBα

    PMID:8599092 PMID:8663605

    Open questions at the time
    • Direct physiological substrates unproven (IκBα phosphorylation only in vitro)
    • Upstream activating kinase unknown
  4. 1997 High

    Defined the proximal receptor complex composition, establishing IRAK1 at the apex of an IL-1R/MyD88/IRAK-2 signaling assembly.

    Evidence Co-IP and dominant-negative epistasis with NF-κB reporter assays

    PMID:9374458

    Open questions at the time
    • Order of assembly and activation step undefined
    • How IRAK1 leaves the complex unknown
  5. 1998 High

    Revealed an autoregulatory feedback loop in which kinase autophosphorylation governs receptor and adaptor binding, explaining signal termination.

    Evidence In vitro binding and autophosphorylation kinase assays with recombinant Pelle and Toll/Tube

    PMID:9806920

    Open questions at the time
    • Conservation of Toll-direct phosphorylation in mammals not shown
    • Single-lab in vitro reconstitution
  6. 1999 High

    Determined the structural basis of kinase recruitment by solving the death-domain heterodimer and measuring its affinity, validating the interface as functionally essential.

    Evidence X-ray crystallography of Pelle-Tube death-domain bundle, SPR/AUC/ITC affinity measurement, and in vivo mutagenesis

    PMID:10330490 PMID:10512628 PMID:10589682

    Open questions at the time
    • Mammalian Myddosome geometry not yet addressed
    • Role of oligomerization beyond membrane association partially defined
  7. 2002 High

    Established the upstream kinase relationship and the activation mechanism, showing IRAK4 phosphorylates and is required to activate IRAK1, and that autophosphorylation potentiates kinase activity.

    Evidence In vitro IRAK4-on-IRAK1 phosphorylation assay with dominant-negative epistasis; concentration-dependent Pelle autophosphorylation kinase assays

    PMID:11731453 PMID:11934858 PMID:11960013

    Open questions at the time
    • Whether activation is covalent or allosteric not yet distinguished
    • Distinct kinase-dependent vs kinase-independent outputs unresolved
  8. 2002 High

    Defined the principal physiological brake on IRAK1 signaling, showing IRAK-M prevents IRAK1 dissociation from MyD88 and blocks IRAK1-TRAF6 complex formation.

    Evidence IRAK-M knockout mice with Co-IP of IRAK1 complexes and cytokine/tolerance phenotyping

    PMID:12150927

    Open questions at the time
    • Molecular mechanism of complex stabilization not structurally defined
    • Other negative regulators not yet known
  9. 2008 Medium

    Uncovered a nuclear role for IRAK1, showing it directly modifies chromatin at NF-κB target genes to enhance transcription.

    Evidence Nuclear fractionation, ChIP at the IκBα promoter, and in vitro/in vivo histone H3 S10 kinase assay

    PMID:18276832

    Open questions at the time
    • Nuclear translocation mechanism unknown
    • Genome-wide chromatin targets not mapped
    • Single lab
  10. 2010 High

    Identified a direct IRAK1 substrate, showing IRAK1 phosphorylates the TLR adaptor Mal to drive its degradation, providing a kinase-dependent feedback on signaling.

    Evidence In vitro kinase assay with kinase-dead controls, ubiquitination assay, inhibitor and siRNA validation

    PMID:20400509

    Open questions at the time
    • In vivo significance of Mal turnover not quantified
    • Single lab
  11. 2011 High

    Defined the deubiquitinase that resets IRAK1, showing A20 removes K63-linked ubiquitin from IRAK1 during endotoxin tolerance and disrupts downstream platform assembly.

    Evidence Co-IP, K63 ubiquitination assays, and A20 shRNA rescue in THP1 cells and human monocytes

    PMID:21220427

    Open questions at the time
    • Direct A20 catalysis on IRAK1 inferred from association
    • Site of K63 linkage on IRAK1 not mapped here
  12. 2013 High

    Expanded IRAK1 output to inflammasome control, showing kinase activity is required for rapid priming-independent NLRP3 activation.

    Evidence IRAK1-deficient macrophages with caspase-1 cleavage, pyroptosis, NLRP3 complex IP, and inhibitor validation

    PMID:24379360

    Open questions at the time
    • Direct IRAK1 substrate within the NLRP3 module unknown
    • Single lab
  13. 2017 High

    Resolved the long-standing question of how IRAK1 is activated, showing the IRAK1 kinase domain is monomeric and is licensed allosterically by heterodimerization with phosphorylated IRAK4 rather than by a single covalent mark.

    Evidence Crystal structure of human IRAK1 kinase domain, SEC dimerization assays, and phosphatase/deubiquitylase-resistant activation in multiple human cell types using Pellino1 substrate assays

    PMID:28512203 PMID:29208712

    Open questions at the time
    • Precise allosteric conformational change not visualized
    • Relationship between allosteric activation and downstream ubiquitination not fully integrated
  14. 2003 Medium

    Identified an additional upstream regulatory input, with atypical PKCι phosphorylating IRAK1 at Thr66 to support autokinase activity and NF-κB signaling.

    Evidence In vitro kinase assay, T66A mutagenesis, Co-IP, and NF-κB reporter

    PMID:14684752

    Open questions at the time
    • Physiological contexts requiring PKCι input not delineated
    • Single lab
  15. 2017 High

    Defined a ubiquitin-dependent trafficking step and its regulation, showing β-TrCP-mediated K48 ubiquitination at Lys134 drives TLR9-induced IRAK1 membrane-to-cytoplasm trafficking and that the glucocorticoid receptor suppresses this.

    Evidence Co-IP, site-specific ubiquitination mapping with K134 mutation, macrophage GR knockout, and NF-κB/MAPK readouts

    PMID:29038250

    Open questions at the time
    • TLR-specificity mechanism (TLR9 vs TLR4) not fully explained
    • Single lab
  16. 2019 Medium

    Linked IRAK1 signaling to antiviral metabolism, showing viperin bridges IRAK1 and TRAF6 to enable IRAK1 K63-ubiquitination and stimulate viperin enzymatic activity.

    Evidence Reciprocal Co-IP and viperin activity reconstitution with ubiquitination assays in HEK293T

    PMID:30872404

    Open questions at the time
    • In vivo relevance to antiviral defense not established
    • Single lab
  17. 2019 High

    Established a non-canonical, MyD88-independent IRAK1 function in radioresistance requiring PIN1 and blocking PIDDosome-mediated apoptosis.

    Evidence Genetic IRAK1 inhibition/KO in tumor models, epistasis with MyD88/TRAF6/IRAK4, caspase-2/PIDDosome assays, and pharmacological IRAK1-PIN1 co-inhibition in xenografts

    PMID:30664786

    Open questions at the time
    • Mechanism of PIN1-dependent IRAK1 activation undefined
    • Single lab
  18. 2015 Medium

    Connected IRAK1 to apoptosis control through both a kinase-substrate route in flies and an anti-apoptotic stabilization route in cancer cells.

    Evidence Pelle-dFoxO Co-IP, in vitro kinase assay and Drosophila genetics; IRAK1/4 knockdown with TRAF6 K63-ubiquitination and MCL1 stability assays in T-ALL

    PMID:25642772 PMID:26474173

    Open questions at the time
    • Conservation of dFoxO phosphorylation in mammals not shown
    • Whether MCL1 stabilization requires IRAK1 kinase activity not resolved
  19. 2021 Medium

    Defined oncogenic IRAK1 roles spanning immune evasion, radioresistance via PRDX1 stabilization, and scaffolding-dependent survival, separating catalytic from non-catalytic functions.

    Evidence CRISPR IRAK1 KO with immune-depletion epistasis; Co-IP/GST pulldown/MS for PRDX1-HECTD3 axis; IRAK1 PROTAC degraders vs kinase inhibitors in MyD88-mutant DLBCL

    PMID:34279092 PMID:34906138 PMID:37031183

    Open questions at the time
    • Generality of scaffolding-vs-kinase dependence across tumor types unclear
    • Each finding from a single lab
  20. 2023 Medium

    Established functional redundancy with IRAK4 in leukemia, showing IRAK4 inhibition triggers IRAK1 compensation and that dual targeting collapses leukemic stem-cell programs.

    Evidence Genetic knockdown/KO, dual IRAK1/4 inhibitor, proteomics, MyD88 epistasis, and patient-derived xenograft models

    PMID:37172199

    Open questions at the time
    • Direct molecular link from IRAK1 to PRC2/JAK-STAT not defined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IRAK1's allosteric kinase activation, K63/K48 ubiquitination states, nuclear chromatin function, and scaffolding-only roles are integrated into a single regulated cycle, and which functions depend on catalysis versus scaffolding in each disease context, remains unresolved.
  • No unified structural model of the activated Myddosome with IRAK1 in human cells
  • Comprehensive in vivo substrate map lacking
  • Kinase-dependent vs scaffolding contributions not systematically separated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 4 GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-74160 Gene expression (Transcription) 1
Partners
IRAK2IRAK4MYD88PIN1PRDX1PRKCITRAF6TUBE
Complex memberships
IRAK1-TRAF6 complexMyddosome (MyD88-IRAK4-IRAK1)NLRP3 inflammasome

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 IRAK1 (IRAK) was identified as a serine/threonine protein kinase that rapidly associates with the IL-1 receptor type I complex upon IL-1 stimulation and becomes phosphorylated, linking IL-1R engagement to NF-κB activation. Protein purification, cDNA cloning, co-immunoprecipitation with IL-1RI complex, phosphorylation assay in HEK293 and HeLa cells Science High 8599092
1993 The Drosophila IRAK1 ortholog Pelle encodes a serine/threonine protein kinase whose catalytic domain is required for biological activity (nuclear import of Dorsal to establish dorsoventral polarity); site-directed mutagenesis of the kinase domain abolishes function. Molecular cloning, DNA sequence analysis, microinjection of in vitro-synthesized transcripts with site-directed mutations in Drosophila embryos Cell High 8440018
1994 Pelle (Drosophila IRAK1 ortholog) functions downstream of Tube in the Toll signaling pathway; Pelle and Tube interact directly, and Tube activates Pelle, as shown by gain-of-function alleles and direct protein interaction. Genetic epistasis with gain-of-function alleles, direct protein-protein interaction assay in Drosophila embryos Nature High 7527496
1995 Pelle (Drosophila IRAK1 ortholog) is recruited to the plasma membrane via interaction with Tube; membrane targeting of Pelle catalytic domain alone is sufficient to induce ventral fates, and Tube-Pelle interaction is required for signal transduction downstream of Toll. Immunolocalization, yeast two-hybrid, membrane-targeted fusion protein assay in Drosophila embryos Development High 7635064
1997 IRAK1 functions as a proximal mediator of IL-1R-induced NF-κB activation, forming a signaling complex with IL-1R, IRAK-2, and MyD88; dominant-negative forms of IRAK-2 or MyD88 attenuate IL-1R-mediated NF-κB activation, establishing IRAK1 at the apex of this complex. Co-immunoprecipitation, dominant-negative overexpression, NF-κB reporter assay Science High 9374458
1998 Pelle (Drosophila IRAK1) directly binds the Toll intracytoplasmic domain; Pelle autophosphorylation prevents binding to both Toll and Tube; Pelle phosphorylates Toll within the Pelle-interaction region, providing a regulatory feedback mechanism. In vitro binding assay with recombinant proteins, autophosphorylation kinase assay, deletion mapping Development High 9806920
1999 The crystal structure of the Pelle–Tube death domain heterodimer was solved; the two death domains form a six-helix bundle in a linear array, with the Tube death domain having an insertion and C-terminal tail making critical contacts; in vivo mutagenesis confirmed that the major heterodimer interface is essential for activity. X-ray crystallography, in vivo functional mutagenesis in Drosophila Cell High 10589682
1999 Pelle and Tube death domains form a heterodimeric complex in vitro with a Kd of ~0.5 µM, as demonstrated by yeast two-hybrid, purified protein interaction, surface plasmon resonance, analytical ultracentrifugation, and isothermal titration calorimetry; mutant Tube proteins unable to support signaling also fail to bind Pelle. Yeast two-hybrid, protein purification, surface plasmon resonance, analytical ultracentrifugation, isothermal titration calorimetry Biochemistry High 10512628
1999 Pelle oligomerization (not membrane association alone) is required for its full activation during Toll signaling; the novel protein Pellino associates with the kinase domain of Pelle. Deletion analysis, oligomerization assays, co-immunoprecipitation in Drosophila cells Mechanisms of development Medium 10330490
1996 Mouse IRAK1 ortholog (mPLK) is a protein kinase that can autophosphorylate and phosphorylate IκBα in vitro, linking it biochemically to NF-κB regulation. Recombinant protein expression in bacteria, in vitro kinase assay The Journal of biological chemistry Medium 8663605
2001 Pelle (Drosophila IRAK1) physically and functionally interacts with dTRAF2 (homolog of human TRAF6); Pelle phosphorylates dTRAF2 in vitro, and co-expression of Pelle and dTRAF2 synergistically activates Dorsal/NF-κB in Schneider cells. Co-immunoprecipitation, in vitro kinase assay, co-transfection NF-κB reporter assay Proceedings of the National Academy of Sciences of the United States of America High 11447260
2001 Pelle (Drosophila IRAK1) functions as a feedback regulator that downregulates Tube plasma membrane recruitment; kinase-inactive Pelle or elimination of Tube-Pelle interaction dramatically increases Tube recruitment to the ventral membrane. Confocal immunofluorescence microscopy, allelic series analysis, autophosphorylation and Tube phosphorylation assays Development High 11731453
2002 Pelle (Drosophila IRAK1) undergoes concentration-dependent autophosphorylation that is enhanced by activated Toll signaling; autophosphorylated Pelle is far more active in vitro than unphosphorylated Pelle, establishing autophosphorylation as the activation mechanism. In vitro kinase assay with recombinant Pelle, transfected Schneider cell phosphorylation assay, gain-of-function Toll mutant analysis Development High 11934858
2002 IRAK-4 phosphorylates IRAK1 and is required upstream of IRAK1 for IL-1-induced activation and modification of IRAK1; overexpression of dominant-negative IRAK-4 blocks IL-1-induced activation of IRAK1. In vitro kinase assay (IRAK-4 phosphorylates IRAK1), dominant-negative overexpression, co-immunoprecipitation in a stimulus-dependent manner Proceedings of the National Academy of Sciences of the United States of America High 11960013
2002 IRAK-M prevents dissociation of IRAK1 and IRAK-4 from MyD88 and blocks formation of IRAK1-TRAF6 complexes, thereby negatively regulating TLR/IL-1R signaling; IRAK-M-deficient cells show increased cytokine production and reduced endotoxin tolerance. Genetic knockout (IRAK-M-/- mice), co-immunoprecipitation of IRAK1-MyD88 and IRAK1-TRAF6 complexes, cytokine measurement Cell High 12150927
2004 IRAK-4 kinase activity is required for optimal recruitment and activation of IRAK1 upon IL-1 stimulation; IRAK-4-deficient cells reconstituted with kinase-inactive IRAK-4 show impaired IRAK1 activation, NF-κB and JNK signaling, though some signals remain kinase-independent. IRAK-4-deficient cell reconstitution with wild-type or kinase-inactive IRAK-4, IRAK1 activation assay, NF-κB and JNK reporter assays The Journal of biological chemistry High 15292196
2001 IRAK1's death domain (but not its kinase activity) is required for NF-κB activation in response to IL-18; the N-proximal undetermined region of IRAK1 is required for NF-κB but not JNK activation in response to IL-18, indicating IRAK1 is a signaling branchpoint; TAK1/TAB1 acts downstream of IRAK1 in IL-18 signaling. IRAK1-deficient mutant cell line (I1A), domain-deletion mutant analysis, dominant-negative TAK1 overexpression, TAB1 phosphorylation assay European journal of immunology Medium 11745395
2008 IRAK1 translocates to the nucleus upon IL-1 or LPS stimulation, binds the promoter of the NF-κB-regulated gene IκBα, enhances NF-κB p65 binding to the IκBα promoter, and phosphorylates histone H3 at serine 10 in vitro and in vivo, revealing a nuclear function for IRAK1 in NF-κB transcriptional activation. Nuclear fractionation, chromatin immunoprecipitation (ChIP), in vitro histone H3 kinase assay, NF-κB transcriptional reporter assay FASEB journal Medium 18276832
2010 Both IRAK1 and IRAK4 directly phosphorylate the TLR adaptor Mal (MyD88 adaptor-like), and this phosphorylation promotes ubiquitination and proteasomal degradation of Mal; kinase-inactive forms of either IRAK have no effect on Mal degradation, establishing Mal as a substrate. In vitro kinase assay (IRAK1/IRAK4 phosphorylate Mal), co-expression ubiquitination assay, IRAK1/4 inhibitor treatment, siRNA knockdown The Journal of biological chemistry High 20400509
2011 Endotoxin tolerance ablates K63-linked polyubiquitination of IRAK1 and TRAF6, compromises assembly of IRAK1-TRAF6 and IRAK1-IKKγ signaling platforms, and this coincides with increased A20 expression and sustained A20-IRAK1 associations; A20 shRNA knockdown abolishes LPS tolerance, establishing A20 as the deubiquitinase that targets IRAK1 ubiquitination. Co-immunoprecipitation, ubiquitination assay (K63-linked), A20 overexpression/shRNA knockdown, NF-κB reporter assay in THP1 cells and human monocytes The Journal of biological chemistry High 21220427
2013 IRAK1 kinase activity is required for TLR-triggered rapid (priming-independent) NLRP3 inflammasome activation; IRAK1-deficient macrophages show compromised rapid caspase-1 cleavage, pyroptosis, and NLRP3 complex assembly upon simultaneous TLR and NLRP3 activation by Listeria monocytogenes. IRAK1-deficient macrophages (genetic KO), caspase-1 cleavage assay, pyroptosis assay, NLRP3 complex immunoprecipitation, pharmacological kinase inhibition Proceedings of the National Academy of Sciences of the United States of America High 24379360
2013 Pelle (Drosophila IRAK1) acts as an IκB kinase (IKK) functional equivalent in the Toll pathway, directly phosphorylating Cactus (IκBα homolog) to trigger its βTrCP/Slimb-dependent ubiquitination and proteasomal degradation, enabling Dorsal nuclear entry. Genetic epistasis, Cactus phosphorylation assay, Slimb (βTrCP) requirement assay in cultured Drosophila cells PloS one Medium 24086459
2017 The crystal structure of the human IRAK1 kinase domain in complex with a small-molecule inhibitor was solved; the IRAK1 kinase domain is constitutively monomeric regardless of phosphorylation state (unlike IRAK4 which homodimerizes when unphosphorylated); phosphorylated IRAK4 kinase domain forms heterodimers with IRAK1 kinase domain, revealing a two-step activation mechanism in the Myddosome. X-ray crystallography, size-exclusion chromatography, phosphorylation-state controlled heterodimer assay Proceedings of the National Academy of Sciences of the United States of America High 29208712
2017 IRAK1 is inactive in unstimulated cells and is activated by IL-1 or TLR stimulation in human cells; this activation is not prevented by pharmacological IRAK4 inhibition and is not reversed by dephosphorylation/deubiquitylation, suggesting IRAK1 is activated by an allosteric mechanism induced by its interaction with IRAK4 rather than by a covalent modification. Novel cell-extract kinase assays using Pellino1 as substrate, specific pharmacological IRAK1/IRAK4 inhibitors, phosphatase/deubiquitylase treatment in HEK293, THP1 monocytes, primary human macrophages The Biochemical journal High 28512203
2003 Atypical protein kinase C iota (PKCι) phosphorylates IRAK1 at Thr66 within the death domain; mutation of Thr66 to Ala impairs IRAK1 autokinase activity and reduces PKCι-IRAK1 association, impairing NGF- and IL-1-induced NF-κB activation; PKCι lies upstream of IRAK1 in the NF-κB pathway. In vitro kinase assay (PKCι phosphorylates IRAK1 peptide), site-directed mutagenesis (T66A), co-immunoprecipitation, NF-κB reporter assay The Journal of biological chemistry Medium 14684752
2017 K48-linked ubiquitination of IRAK1 at Lys134 by β-TrCP is required for TLR9-induced IRAK1 membrane-to-cytoplasm trafficking and downstream NF-κB/MAPK activation; glucocorticoid receptor physically interacts with IRAK1 and interferes with β-TrCP-IRAK1 interaction to suppress TLR9-specific (not TLR4) inflammation. Co-immunoprecipitation (GR-IRAK1 interaction), ubiquitination assay (K48-linked at Lys134), IRAK1 K134 mutation, macrophage glucocorticoid receptor knockout, NF-κB/MAPK activation assays Journal of immunology High 29038250
2019 Viperin interacts with both IRAK1 and TRAF6; IRAK1 and TRAF6 together stimulate viperin enzymatic activity ~10-fold; TRAF6-mediated K63-linked ubiquitination of IRAK1 requires the association of viperin with both IRAK1 and TRAF6, coupling innate immune signaling to antiviral ddhCTP synthesis. Co-immunoprecipitation (viperin-IRAK1-TRAF6 in HEK293T), viperin activity reconstitution assay, ubiquitination assay The Journal of biological chemistry Medium 30872404
2019 IRAK1 drives radiotherapy resistance via a pathway involving IRAK4 and TRAF6, but not MyD88; radiation-activated IRAK1 prevents PIDDosome-mediated caspase-2 apoptosis; IRAK1 requires PIN1 (a prolyl isomerase) for its activation in response to ionizing radiation. Genetic IRAK1 inhibition/KO in tumor models, epistasis with MyD88/TRAF6/IRAK4 knockdown, caspase-2 and PIDDosome assays, pharmacological IRAK1-PIN1 co-inhibition in xenograft models Nature cell biology High 30664786
2015 IRAK1/4 signaling activates the E3 ubiquitin ligase TRAF6, increasing K63-linked ubiquitination and enhancing stability of the antiapoptotic protein MCL1; IRAK inhibition reduces MCL1 stability, sensitizing T-ALL cells to apoptosis-inducing combination therapy. shRNA knockdown of IRAK1/IRAK4, pharmacological IRAK1/4 inhibition, K63-ubiquitination assay of TRAF6, MCL1 stability assay, leukemia xenograft model The Journal of clinical investigation Medium 25642772
2023 In MDS/AML, IRAK1 and IRAK4 operate via noncanonical MyD88-independent pathways; inhibiting IRAK4 elicits functional compensation by IRAK1; combined IRAK1+IRAK4 cotargeting suppresses leukemic stem/progenitor cell function and induces differentiation; IRAK1/IRAK4 preserve the undifferentiated state through pathways converging on PRC2 and JAK-STAT signaling. Genetic knockdown/knockout, dual IRAK1/4 inhibitor (KME-2780), proteomics, MyD88 genetic epistasis, xenograft and patient-derived cell models Blood Medium 37172199
2021 In FGFR1-driven hematological malignancies (SCLL), IRAK1 promotes immune evasion by regulating IFN-γ production from leukemia cells, which induces MDSC expansion to suppress T cell-mediated tumor killing; IRAK1 KO eliminates disease in immunocompetent but not immunodeficient mice. CRISPR/Cas9 IRAK1 knockout, syngeneic xenograft, T-cell depletion, IFNG KO cells, IFNGR1-null host mice, cytokine profiling Molecular cancer Medium 34906138
2021 IRAK1 binds to PRDX1 and prevents its ubiquitination and degradation by E3 ubiquitin ligase HECTD3 (whose DOC and HECT domains both interact with PRDX1), thereby promoting radioresistance in glioma by suppressing autophagic cell death. Co-IP, LC-MS/MS, GST pull-down, ubiquitination assay, IRAK1 knockdown with in vitro and in vivo radiosensitivity assays, ChIP and dual-luciferase for FOXA2-IRAK1 transcription axis Cell death & disease Medium 37031183
2021 IRAK1 scaffolding function (rather than kinase activity) is required for survival of ABC DLBCL cells harboring MyD88 mutation; IRAK1-targeted degraders (PROTACs) potently degrade IRAK1 and inhibit downstream NF-κB signaling and cell proliferation. IRAK1 PROTAC degraders, cell viability assays, NF-κB pathway reporter assay in MyD88-mutant ABC DLBCL cells Journal of medicinal chemistry Medium 34279092
2015 Pelle (Drosophila IRAK1) physically interacts with dFoxO and directly phosphorylates dFoxO, promoting its cytoplasmic-to-nuclear translocation and upregulation of Thor/4E-BP transcription, revealing a Toll-independent role for Pelle in regulating apoptotic cell death. Co-immunoprecipitation (Pelle-dFoxO), in vitro kinase assay (Pelle phosphorylates dFoxO), nuclear translocation assay, genetic loss-of-function in Drosophila wing tissue PLoS genetics Medium 26474173

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 1120 12150927
1997 IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science (New York, N.Y.) 944 9374458
1996 IRAK: a kinase associated with the interleukin-1 receptor. Science (New York, N.Y.) 743 8599092
2002 Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 628 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
2003 Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. Molecular cell 451 12620219
1999 IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family. The Journal of biological chemistry 343 10383454
2010 Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 319 21057262
2009 Evolutionary history and stress regulation of plant receptor-like kinase/pelle genes. Plant physiology 298 19321712
2011 Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IκBα deficiency. Clinical microbiology reviews 294 21734245
2013 IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation. Proceedings of the National Academy of Sciences of the United States of America 234 24379360
2007 IRAK1: a critical signaling mediator of innate immunity. Cellular signalling 225 17890055
1993 pelle encodes a protein kinase required to establish dorsoventral polarity in the Drosophila embryo. Cell 191 8440018
2011 The RLK/Pelle family of kinases. The Plant journal : for cell and molecular biology 178 21443627
2002 IRAK-4 as the central TIR signaling mediator in innate immunity. Trends in immunology 169 12297423
1999 Three-dimensional structure of a complex between the death domains of Pelle and Tube. Cell 145 10589682
2012 Experimental and natural infections in MyD88- and IRAK-4-deficient mice and humans. European journal of immunology 139 23255009
2023 MiR146a-loaded engineered exosomes released from silk fibroin patch promote diabetic wound healing by targeting IRAK1. Signal transduction and targeted therapy 137 36775818
2014 IRAK signalling in cancer. British journal of cancer 134 25290089
2009 IRAK-4 inhibitors for inflammation. Current topics in medicinal chemistry 120 19689377
1994 Activation of the kinase Pelle by Tube in the dorsoventral signal transduction pathway of Drosophila embryo. Nature 115 7527496
2018 Inhibition of interleukin-1 receptor-associated kinase 1 (IRAK1) as a therapeutic strategy. Oncotarget 113 30279971
2013 IRAK-M mediates Toll-like receptor/IL-1R-induced NFκB activation and cytokine production. The EMBO journal 113 23376919
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
1999 Oligomerisation of Tube and Pelle leads to nuclear localisation of dorsal. Mechanisms of development 111 10330490
2017 Thymoquinone: An IRAK1 inhibitor with in vivo and in vitro anti-inflammatory activities. Scientific reports 104 28216638
2018 IRAK1 Augments Cancer Stemness and Drug Resistance via the AP-1/AKR1B10 Signaling Cascade in Hepatocellular Carcinoma. Cancer research 92 29483095
2015 Human Cytomegalovirus miR-UL112-3p Targets TLR2 and Modulates the TLR2/IRAK1/NFκB Signaling Pathway. PLoS pathogens 91 25955717
2023 Regulation of innate immune signaling by IRAK proteins. Frontiers in immunology 84 36865541
2020 IRAK family in inflammatory autoimmune diseases. Autoimmunity reviews 82 31917263
2022 IRAK1 and IRAK4 as emerging therapeutic targets in hematologic malignancies. Current opinion in hematology 77 34743084
2011 Endotoxin tolerance impairs IL-1 receptor-associated kinase (IRAK) 4 and TGF-beta-activated kinase 1 activation, K63-linked polyubiquitination and assembly of IRAK1, TNF receptor-associated factor 6, and IkappaB kinase gamma and increases A20 expression. The Journal of biological chemistry 77 21220427
2017 The mechanism of activation of IRAK1 and IRAK4 by interleukin-1 and Toll-like receptor agonists. The Biochemical journal 73 28512203
1995 Interaction of the pelle kinase with the membrane-associated protein tube is required for transduction of the dorsoventral signal in Drosophila embryos. Development (Cambridge, England) 68 7635064
1993 Genetic characterization of tube and pelle, genes required for signaling between Toll and dorsal in the specification of the dorsal-ventral pattern of the Drosophila embryo. Genetics 67 8244004
2017 Crystal structure of human IRAK1. Proceedings of the National Academy of Sciences of the United States of America 65 29208712
2015 Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies. The Journal of clinical investigation 65 25642772
2010 IRAK-M regulation and function in host defense and immune homeostasis. Infectious disease reports 65 21390243
2013 IRAK1/4-targeted anti-inflammatory action of caffeic acid. Mediators of inflammation 64 24379523
2001 Physical and functional interactions between Drosophila TRAF2 and Pelle kinase contribute to Dorsal activation. Proceedings of the National Academy of Sciences of the United States of America 63 11447260
2007 NF-kappaB, IkappaB, and IRAK control glutamate receptor density at the Drosophila NMJ. Neuron 60 17880891
2006 IRAK-4--a shared NF-kappaB activator in innate and acquired immunity. Trends in immunology 60 17046325
2014 IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens. Blood 57 25320238
2021 SARS-CoV-2/ACE2 Interaction Suppresses IRAK-M Expression and Promotes Pro-Inflammatory Cytokine Production in Macrophages. Frontiers in immunology 56 34248968
2008 Interleukin-1 receptor-associated kinase (IRAK) -1-mediated NF-kappaB activation requires cytosolic and nuclear activity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 55 18276832
2023 MicroRNA-146a negatively regulates inflammation via the IRAK1/TRAF6/NF-κB signaling pathway in dry eye. Scientific reports 52 37433841
2010 IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal). The Journal of biological chemistry 52 20400509
2019 Viperin interacts with the kinase IRAK1 and the E3 ubiquitin ligase TRAF6, coupling innate immune signaling to antiviral ribonucleotide synthesis. The Journal of biological chemistry 49 30872404
2001 The protein kinase Pelle mediates feedback regulation in the Drosophila Toll signaling pathway. Development (Cambridge, England) 49 11731453
2018 miR-146a promotes cervical cancer cell viability via targeting IRAK1 and TRAF6. Oncology reports 48 29693168
2019 An IRAK1-PIN1 signalling axis drives intrinsic tumour resistance to radiation therapy. Nature cell biology 47 30664786
2012 Molecular evolution and structural features of IRAK family members. PloS one 47 23166766
2000 The Drosophila tumor necrosis factor receptor-associated factor-1 (DTRAF1) interacts with Pelle and regulates NFkappaB activity. The Journal of biological chemistry 47 10766844
1998 Phosphorylation modulates direct interactions between the Toll receptor, Pelle kinase and Tube. Development (Cambridge, England) 46 9806920
2023 Paralog-specific signaling by IRAK1/4 maintains MyD88-independent functions in MDS/AML. Blood 45 37172199
2020 Investigational IRAK-4 inhibitors for the treatment of rheumatoid arthritis. Expert opinion on investigational drugs 44 32255710
1998 Recruitment of Tube and Pelle to signaling sites at the surface of the Drosophila embryo. Development (Cambridge, England) 44 9609827
2023 Selenium alleviates lead-induced CIK cells pyroptosis and inflammation through IRAK1/TAK1/IKK pathway. Fish & shellfish immunology 42 37758100
1996 Functional interactions between the pelle kinase, Toll receptor, and tube suggest a mechanism for activation of dorsal. Genes & development 39 8846922
2019 BAP31 regulates IRAK1-dependent neuroinflammation in microglia. Journal of neuroinflammation 38 31883536
2009 Toll-like receptor responses in IRAK-4-deficient neutrophils. Journal of innate immunity 38 20375545
2016 Epigenetic and Transcriptional Regulation of IRAK-M Expression in Macrophages. Journal of immunology (Baltimore, Md. : 1950) 37 28011933
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
2015 IRAK1 mediates TLR4-induced ABCA1 downregulation and lipid accumulation in VSMCs. Cell death & disease 34 26512959
2008 IRAK-4 kinase activity-dependent and -independent regulation of lipopolysaccharide-inducible genes. European journal of immunology 33 18266302
2023 Radiation induces IRAK1 expression to promote radioresistance by suppressing autophagic cell death via decreasing the ubiquitination of PRDX1 in glioma cells. Cell death & disease 32 37031183
2013 The IRAK homolog Pelle is the functional counterpart of IκB kinase in the Drosophila Toll pathway. PloS one 32 24086459
1996 Developmental and tissue-specific expression of mouse pelle-like protein kinase. The Journal of biological chemistry 32 8663605
2021 Targeting the IRAK1-S100A9 Axis Overcomes Resistance to Paclitaxel in Nasopharyngeal Carcinoma. Cancer research 31 33402387
2008 Down-regulation of IRAK-4 is a component of LPS- and CpG DNA-induced tolerance in macrophages. Cellular signalling 31 18992325
2013 Association of an activity-enhancing variant of IRAK1 and an MECP2-IRAK1 haplotype with increased susceptibility to rheumatoid arthritis. Arthritis and rheumatism 30 23233309
2007 Inherited human IRAK-4 deficiency: an update. Immunologic research 30 17917042
2002 Pelle kinase is activated by autophosphorylation during Toll signaling in Drosophila. Development (Cambridge, England) 30 11934858
2021 IRAK1-regulated IFN-γ signaling induces MDSC to facilitate immune evasion in FGFR1-driven hematological malignancies. Molecular cancer 29 34906138
2001 IRAK and TAK1 are required for IL-18-mediated signaling. European journal of immunology 26 11745395
2023 IRAK-M suppresses the activation of microglial NLRP3 inflammasome and GSDMD-mediated pyroptosis through inhibiting IRAK1 phosphorylation during experimental autoimmune encephalomyelitis. Cell death & disease 25 36765034
2018 Expression of microRNAs and IRAK1 pathway genes are altered in gastric cancer patients with Helicobacter pylori infection. Journal of cellular biochemistry 25 29797599
2014 PKCδ-IRAK1 axis regulates oxidized LDL-induced IL-1β production in monocytes. Journal of lipid research 25 24792928
2014 Expression of IRAK1 in lung cancer tissues and its clinicopathological significance: a microarray study. International journal of clinical and experimental pathology 25 25550857
2022 Eliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors. Nature communications 24 35022428
2019 A highly selective inhibitor of interleukin-1 receptor-associated kinases 1/4 (IRAK-1/4) delineates the distinct signaling roles of IRAK-1/4 and the TAK1 kinase. The Journal of biological chemistry 24 31914413
2018 Upregulated IL-1 Receptor-associated Kinase 1 (IRAK1) in Systemic Lupus Erythematosus: IRAK1 Inhibition Represses Th17 Differentiation with Therapeutic Potential. Immunological investigations 24 29611775
2005 Novel role and regulation of the interleukin-1 receptor associated kinase (IRAK) family proteins. Cellular & molecular immunology 24 16212909
2016 G2013 modulates TLR4 signaling pathway in IRAK-1 and TARF-6 dependent and miR-146a independent manner. Cellular and molecular biology (Noisy-le-Grand, France) 23 27188726
2007 A gain-of-function screen for genes that influence axon guidance identifies the NF-kappaB protein dorsal and reveals a requirement for the kinase Pelle in Drosophila photoreceptor axon targeting. Genetics 23 17603113
2023 IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies. Frontiers in immunology 22 37954584
2021 Discovery of Highly Potent and Selective IRAK1 Degraders to Probe Scaffolding Functions of IRAK1 in ABC DLBCL. Journal of medicinal chemistry 22 34279092
2017 Inhibition of IRAK1 Ubiquitination Determines Glucocorticoid Sensitivity for TLR9-Induced Inflammation in Macrophages. Journal of immunology (Baltimore, Md. : 1950) 22 29038250
2017 Critical Role of IRAK-M in Regulating Antigen-Induced Airway Inflammation. American journal of respiratory cell and molecular biology 21 28665693
2016 IRAK regulates macrophage foam cell formation by modulating genes involved in cholesterol uptake and efflux. BioEssays : news and reviews in molecular, cellular and developmental biology 21 27270491
2022 miR-146a contributes to atherosclerotic plaque stability by regulating the expression of TRAF6 and IRAK-1. Molecular biology reports 20 35195809
2013 IRAK-M expression limits dendritic cell activation and proinflammatory cytokine production in response to Helicobacter pylori. PloS one 20 23776703
2003 Regulation of interleukin receptor-associated kinase (IRAK) phosphorylation and signaling by iota protein kinase C. The Journal of biological chemistry 20 14684752
1999 Formation and biochemical characterization of tube/pelle death domain complexes: critical regulators of postreceptor signaling by the Drosophila toll receptor. Biochemistry 20 10512628
2021 Pharmacological inhibition of IRAK1 and IRAK4 prevents endothelial inflammation and atherosclerosis in ApoE-/- mice. Pharmacological research 19 34954030
2015 Pelle Modulates dFoxO-Mediated Cell Death in Drosophila. PLoS genetics 19 26474173
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
2019 Molecular characterization, expression and functional analysis of IRAK1 and IRAK4 in Nile tilapia (Oreochromis niloticus). Fish & shellfish immunology 18 31846774
2017 Micro RNA-146a But Not IRAK1 is Associated with Rheumatoid Arthritis in the Tunisian Population. Genetic testing and molecular biomarkers 18 28207326

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