Affinage

IRAK1

Interleukin-1 receptor-associated kinase 1 · UniProt P51617

Length
712 aa
Mass
76.5 kDa
Annotated
2026-04-28
100 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IRAK1 is a serine/threonine kinase central to TLR/IL-1R innate immune signaling, functioning both as a catalytic enzyme and as a scaffolding platform that activates NF-κB, inflammasome, and antiviral pathways. Pre-associated with Tollip, IRAK1 is recruited to activated receptor complexes via MyD88, where it is activated through heterodimerization with phosphorylated IRAK4; once activated, IRAK1 dissociates and engages TRAF6 to drive NF-κB and MAPK signaling, phosphorylates Pellino E3 ligases to trigger K63-polyubiquitination of itself and coupling to NEMO/IKK, and phosphorylates the adaptor Mal to promote its degradation (PMID:8599092, PMID:10854325, PMID:17997719, PMID:20400509, PMID:29208712). Beyond canonical NF-κB activation, IRAK1 kinase activity directly links TLR stimulation to rapid NLRP3 inflammasome assembly independent of transcription, activates viperin's radical SAM activity to produce the antiviral nucleotide ddhCTP, and stabilizes MCL1 through TRAF6-mediated K63-ubiquitination (PMID:24379360, PMID:30872404, PMID:25642772). IRAK1's kinase-independent scaffolding function is essential for survival of MyD88-mutant lymphoma cells, and human IRAK1 deficiency selectively impairs TLR signaling in fibroblasts but is largely redundant in leukocytes (PMID:34279092, PMID:28069966).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1996 High

    Identification of IRAK1 as the kinase physically recruited to the IL-1 receptor complex established the first signaling kinase directly linking IL-1R engagement to downstream phosphorylation cascades.

    Evidence Protein purification, cDNA cloning, co-immunoprecipitation with IL-1RI in HEK293/HeLa cells

    PMID:8599092

    Open questions at the time
    • No downstream substrates identified
    • Relationship to NF-κB pathway not yet established
    • No loss-of-function data
  2. 2000 High

    Discovery that Tollip pre-associates with IRAK1 and delivers it to the receptor complex, and that IRAK1 translocates to the nucleus after IL-1 stimulation, revealed the regulated trafficking of IRAK1 through distinct subcellular compartments during signaling.

    Evidence Co-immunoprecipitation, NF-κB reporter assays, subcellular fractionation and confocal microscopy

    PMID:10854325 PMID:10899313

    Open questions at the time
    • Nuclear function of IRAK1 undefined
    • Mechanism of Tollip-IRAK1 dissociation unclear at molecular level
  3. 2002 High

    IRAK-M was shown to negatively regulate signaling by trapping IRAK1/IRAK4 on MyD88 and preventing IRAK1-TRAF6 complex formation, establishing that IRAK1 dissociation from the receptor complex is a regulated and essential signaling step, while IRAK1 was also linked to IL-1-induced PI3K/Akt activation.

    Evidence IRAK-M knockout mice, co-immunoprecipitation of IRAK1/IRAK4/MyD88, IRAK1-deficient cell line phospho-Akt assays

    PMID:12150927 PMID:12516562

    Open questions at the time
    • Direct IRAK1 substrate in PI3K activation unknown
    • Relative contribution of IRAK1 kinase activity vs. scaffolding not resolved
  4. 2008 High

    Reconstitution of IRAK1-Pellino phosphorylation and subsequent K63-polyubiquitination of IRAK1 coupling to NEMO/IKK provided the first complete biochemical pathway from IRAK1 kinase activity to NF-κB complex activation, while genetic studies revealed IRAK1 mediates early-phase TLR responses with IRAK2 sustaining late-phase signaling.

    Evidence In vitro kinase and ubiquitination assays with Ubc13-Uev1a, IRAK1/IRAK2 knockout mice, temporal kinase activity and cytokine measurements

    PMID:17997719 PMID:18438411

    Open questions at the time
    • In vivo validation of Pellino-IRAK1 ubiquitination axis incomplete
    • Structural basis of Pellino-IRAK1 interaction unknown
  5. 2010 High

    Demonstration that IRAK1 directly phosphorylates the TLR adaptor Mal to promote its ubiquitination and degradation identified a negative-feedback substrate distinct from Pellino, showing IRAK1 shapes signal duration by eliminating upstream adaptors.

    Evidence In vitro kinase assay with kinase-dead controls, siRNA and pharmacological inhibitor in LPS-stimulated cells

    PMID:20400509

    Open questions at the time
    • Specific phosphorylation sites on Mal responsible for degradation not fully mapped
    • Relative contribution of IRAK1 vs. IRAK4 in Mal phosphorylation in vivo unclear
  6. 2013 High

    IRAK1 was found to directly link TLR activation to rapid, transcription-independent NLRP3 inflammasome assembly, expanding its role beyond NF-κB to include inflammasome-mediated pyroptosis.

    Evidence IRAK1 knockout macrophages, caspase-1 cleavage and pyroptosis assays, Listeria infection model

    PMID:24379360

    Open questions at the time
    • Direct IRAK1 substrate in inflammasome assembly not identified
    • Whether IRAK1 kinase activity or scaffolding drives inflammasome coupling unresolved
  7. 2015 Medium

    IRAK1/TRAF6 signaling was shown to stabilize MCL1 through K63-ubiquitination, linking IRAK1 to an anti-apoptotic mechanism exploited by cancers including T-ALL and TNBC.

    Evidence shRNA knockdown, IRAK inhibitor, K63-ubiquitination assay for MCL1, xenograft models

    PMID:25642772 PMID:26503059

    Open questions at the time
    • Whether IRAK1 directly phosphorylates MCL1 or acts solely through TRAF6 unclear
    • Generalizability of MCL1 stabilization across tumor types not established
  8. 2017 High

    The crystal structure of the IRAK1 kinase domain revealed it is constitutively monomeric and requires phosphorylated IRAK4 for heterodimerization and activation, establishing a two-step activation model, while human IRAK1 deficiency demonstrated cell-type-specific and largely redundant roles in leukocytes.

    Evidence X-ray crystallography with dimerization assays; patient-derived IRAK1-null fibroblasts and PBMCs stimulated with multiple TLR agonists

    PMID:28069966 PMID:29208712

    Open questions at the time
    • Full-length IRAK1 structure including death domain unavailable
    • Structural basis of IRAK1-TRAF6 interaction not resolved
    • Compensatory mechanisms in leukocytes not defined
  9. 2019 High

    IRAK1 and TRAF6 were shown to activate viperin's radical SAM enzymatic activity to produce the antiviral nucleotide ddhCTP, establishing a direct molecular link between innate immune kinase signaling and antiviral effector molecule synthesis.

    Evidence Co-immunoprecipitation in HEK293T, in vitro ddhCTP enzymatic assay, ubiquitination assay

    PMID:30872404

    Open questions at the time
    • Whether IRAK1 phosphorylates viperin directly not determined
    • In vivo relevance during viral infection not demonstrated
  10. 2021 Medium

    PROTAC-mediated degradation of IRAK1 in MyD88-mutant ABC DLBCL cells demonstrated that IRAK1 scaffolding function, independent of kinase activity, is essential for lymphoma survival, explaining why kinase inhibitors alone are insufficient.

    Evidence PROTAC-mediated IRAK1 degradation vs. kinase inhibitors, cell viability and signaling assays in ABC DLBCL

    PMID:34279092

    Open questions at the time
    • Identity of scaffolding-dependent binding partners in DLBCL not mapped
    • Selectivity of PROTACs for IRAK1 over other IRAKs not fully characterized
  11. 2023 Medium

    IRAK1 was found to protect PRDX1 from HECTD3-mediated ubiquitination, suppressing autophagic death and promoting radioresistance, while dual IRAK1/IRAK4 targeting was shown necessary to suppress leukemic stem cells via noncanonical MyD88-independent pathways including PRC2 and JAK-STAT.

    Evidence Co-IP, GST pull-down, ubiquitination assays, CRISPR/shRNA, xenograft models, proteomic and genomic analyses

    PMID:37031183 PMID:37172199

    Open questions at the time
    • Whether IRAK1-PRDX1 interaction requires kinase activity unknown
    • Noncanonical MyD88-independent substrates of IRAK1 not identified
    • Mechanism of IRAK1/4 convergence on PRC2 not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of IRAK1 with its death domain, the identity of direct IRAK1 substrates in inflammasome assembly and PI3K activation, the molecular basis of its nuclear function, and systematic delineation of kinase-dependent versus scaffolding-dependent roles across cell types.
  • Full-length IRAK1 structure unavailable
  • Nuclear substrates/function undefined
  • Kinase vs. scaffold contributions not systematically resolved across tissues

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 5 R-HSA-5357801 Programmed Cell Death 2
Partners
IRAK3IRAK4MYD88PELI1RSAD2TIRAPTOLLIPTRAF6
Complex memberships
IRAK1-TRAF6 complexMyD88-IRAK4-IRAK1 myddosomeTollip-IRAK1 complex

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 IRAK1 (IRAK) was identified as a serine/threonine kinase that rapidly associates with the IL-1 receptor complex (IL-1RI) upon IL-1 stimulation and undergoes phosphorylation; its primary sequence shares similarity with Drosophila Pelle kinase. Protein purification, cDNA cloning, co-immunoprecipitation with IL-1RI complex, phosphorylation assay in HEK293/HeLa cells Science High 8599092
2000 Tollip forms a pre-existing complex with IRAK1; upon IL-1β stimulation, the Tollip-IRAK1 complex is recruited to the activated IL-1RAcP-containing receptor complex via Tollip, whereupon MyD88 triggers IRAK1 autophosphorylation, leading to rapid dissociation of IRAK1 from Tollip. Co-immunoprecipitation, overexpression in cells, NF-κB reporter assay Nature Cell Biology High 10854325
2002 IRAK-M (IRAK3) prevents dissociation of IRAK1 and IRAK4 from MyD88 and prevents formation of IRAK1-TRAF6 complexes, thereby acting as a negative regulator of TLR/IL-1R signaling. IRAK-M knockout mice, co-immunoprecipitation of IRAK1/IRAK4/MyD88 complexes, cytokine assays Cell High 12150927
2002 IRAK1 is required for IL-1β-induced phosphorylation of PKB/Akt (PI3-K pathway activation), demonstrated using an IRAK-1-deficient cell line. IRAK-1-deficient cell line, phospho-PKB western blot European Journal of Immunology Medium 12516562
2003 IRAK1 mediates Toll/IL-1 signaling in cardiac myocytes; IRAK1-deficient hearts exhibit impaired LPS-triggered downstream signal transduction and resist acute LPS-induced contractile dysfunction. IRAK1 knockout mice, cardiac function assays, LPS challenge American Journal of Physiology. Heart and Circulatory Physiology Medium 12860565
2003 Pellino2 is a substrate of both IRAK1 and IRAK4, and physically interacts with kinase-active and kinase-inactive forms of IRAK1 and IRAK4, suggesting a scaffolding role in TIR signaling. Co-immunoprecipitation, in vitro kinase assay, RNAi knockdown, overexpression FEBS Letters Medium 12860405
2006 IRAK1 splice variants (full-length IRAK1, IRAK1b, IRAK1c) are differentially regulated: full-length IRAK1 undergoes phosphorylation, ubiquitination, and sumoylation (the latter responsible for nuclear translocation), while IRAK1c remains stable, lacks modifications, and is confined to the cytoplasm. Biochemical fractionation, western blot, confocal microscopy, site-directed mutagenesis Molecular Immunology Medium 16690127
2007 IRAK-4-dependent phosphorylation of IRAK-1 promotes IRAK-1 degradation, functioning as a negative feedback mechanism to terminate TLR-induced NF-κB activation; IRAK-4 expression alone is sufficient to cause IRAK-1 degradation independent of IRAK-1 autophosphorylation. IRAK-4-deficient macrophages (shRNA), expression of kinase-dead mutants, western blot for IRAK-1 protein levels Journal of Biochemistry Medium 18079163
2008 IRAK1 and IRAK4 phosphorylate Pellino isoforms in vitro, greatly enhancing Pellino's E3 ubiquitin ligase activity; activated Pellino 1 catalyzes formation of K63-linked polyubiquitin chains on IRAK1 (using Ubc13-Uev1a), and K63-polyubiquitinated IRAK1 interacts with NEMO (IKK regulatory subunit), coupling IRAK1 activation to NF-κB pathway. In vitro kinase assay, in vitro ubiquitination assay, co-immunoprecipitation, co-transfection in IRAK1-/- cells The Biochemical Journal High 17997719
2008 IRAK1 and IRAK2 act sequentially downstream of IRAK4 in TLR signaling: IRAK1 kinase activity is responsible for early-phase TLR responses (within 1 h) while IRAK2 sustains late-phase NF-κB activation (peaking ~8 h); loss of both IRAK1 and IRAK2 abrogates TLR-induced cytokine production. IRAK1 and IRAK2 knockout mice, kinase activity assays, NF-κB reporter, cytokine measurement Nature Immunology High 18438411
2010 IRAK1 and IRAK4 directly phosphorylate Mal (MyD88 adaptor-like/TIRAP), and this phosphorylation promotes ubiquitination and proteasomal degradation of Mal downstream of TLR2 and TLR4 signaling; MyD88 is not a substrate for the IRAKs. In vitro kinase assay, co-expression with kinase-dead mutants, siRNA knockdown, IRAK1/4 pharmacological inhibitor, ubiquitination assay, LPS stimulation The Journal of Biological Chemistry High 20400509
2013 IRAK1 directly links TLR activation to rapid NLRP3 inflammasome assembly in a kinase-activity-dependent manner, independently of new protein synthesis; IRAK-1-deficient macrophages show compromised rapid caspase-1 cleavage and pyroptosis upon simultaneous TLR and NLRP3 activation. IRAK1 knockout macrophages, caspase-1 cleavage assay, pyroptosis assay, Listeria infection model, pharmacological inhibition PNAS High 24379360
2017 Crystal structure of the human IRAK1 kinase domain reveals it is constitutively monomeric (unlike IRAK4 which homodimerizes when unphosphorylated); IRAK1 forms heterodimers with phosphorylated IRAK4 but not unphosphorylated IRAK4, indicating a two-step activation mechanism where IRAK4 homodimerizes and trans-autophosphorylates first, then phosphorylated IRAK4 heterodimerizes with IRAK1 to activate it. X-ray crystallography, kinase domain phosphorylation state assays, dimerization assays PNAS High 29208712
2017 IRAK1 undergoes K48-linked ubiquitination at Lys134 mediated by β-TrCP, which facilitates membrane-to-cytoplasm trafficking of IRAK1 interacting partners TRAF6 and TAK1 and subsequent NF-κB/MAPK activation downstream of TLR9; glucocorticoid receptor physically interacts with IRAK1 and blocks β-TrCP-IRAK1 interaction, selectively suppressing TLR9-induced IRAK1 ubiquitination. Co-immunoprecipitation, site-directed mutagenesis (K134 mutation), ubiquitination assay, GR knockout macrophages, subcellular fractionation Journal of Immunology High 29038250
2017 Human inherited IRAK-1 deficiency selectively impairs TLR (TLR1/2, TLR2/6, TLR4) signaling in fibroblasts but not in leukocytes, whereas IL-1R responses are largely intact in fibroblasts; IRAK-1 plays a redundant role downstream of TLRs and IL-1Rs in leukocytes. Patient-derived cells with IRAK1 deletion, TLR/IL-1R stimulation assays in fibroblasts and PBMCs PNAS High 28069966
2019 Viperin interacts with both IRAK1 and TRAF6; IRAK1 and TRAF6 activate viperin's radical SAM enzymatic activity ~10-fold to produce ddhCTP; TRAF6-mediated K63-ubiquitination of IRAK1 requires the association of viperin with both IRAK1 and TRAF6, coupling innate immune signaling to antiviral nucleotide synthesis. Co-immunoprecipitation in HEK293T, in vitro enzymatic assay for ddhCTP production, ubiquitination assay The Journal of Biological Chemistry High 30872404
2000 IRAK1 translocates to the nucleus upon IL-1 stimulation, with nuclear accumulation detectable 30 min after stimulation, as shown by subcellular fractionation and confocal microscopy. Western blot of nuclear/cytoplasmic fractions, confocal laser scanning microscopy FEBS Letters Medium 10899313
2020 S100A14 promotes ubiquitin-proteasome-mediated degradation of IRAK1, suppressing NF-κB signaling and NPC cell migration; S100A14 and IRAK1 establish a feedback loop disrupted by IRAK1 inhibition. Co-immunoprecipitation, gain/loss-of-function assays, ubiquitination assay, xenograft model Oncogene Medium 32555330
2019 BAP31 modulates IRAK1 protein levels in microglia; BAP31 deficiency upregulates IRAK1 protein and increases IRAK1-dependent NF-κB p65 and c-Jun translocation and transcriptional activity, leading to enhanced neuroinflammatory cytokine production; IRAK1 knockdown or inhibition reverses these effects. BAP31 conditional knockdown mice and BV2 cells, IRAK1 siRNA/inhibitor, NF-κB reporter, western blot, immunofluorescence Journal of Neuroinflammation Medium 31883536
2017 Syk kinase controls IRAK1 transcriptional upregulation and functional activation downstream of TLR4/MyD88 signaling; Syk-knockout RAW264.7 macrophages show near-complete block of LPS-induced IRAK1 activity and expression, restored by Syk re-expression. Syk knockout RAW264.7 cells, pharmacological Syk inhibitor (piceatannol), overexpression, qRT-PCR, western blot Mediators of Inflammation Medium 28680194
2023 IRAK1 and IRAK4 preserve the undifferentiated state of MDS/AML leukemic stem/progenitor cells via noncanonical MyD88-independent pathways, including convergence on the polycomb repressive complex 2 and JAK-STAT signaling; dual cotargeting of IRAK1 and IRAK4 is required to suppress LSPC function. Genetic (shRNA/CRISPR) and pharmacologic (dual inhibitor KME-2780) approaches, proteomic and genomic analyses, xenograft models Blood Medium 37172199
2021 IRAK1 scaffolding function (independent of kinase activity) is required for survival of ABC DLBCL cells harboring MyD88 mutation; IRAK1 degraders (PROTACs) suppress downstream signaling and proliferation more effectively than kinase inhibitors. PROTAC-mediated IRAK1 degradation, cell viability assays, downstream signaling western blot in ABC DLBCL cells Journal of Medicinal Chemistry Medium 34279092
2015 IRAK1 drives breast cancer (TNBC) metastasis and paclitaxel resistance through NF-κB-related cytokine secretion; paclitaxel induces IRAK1 phosphorylation; pharmacologic IRAK1 inhibition reverses paclitaxel resistance at least in part through inhibiting the p38-MCL1 pro-survival pathway. Genetic (siRNA/shRNA) and pharmacological inhibition of IRAK1, xenograft models, western blot for p38-MCL1 pathway Nature Communications Medium 26503059
2015 IRAK1/4 signaling stabilizes the antiapoptotic protein MCL1 via TRAF6-dependent K63-linked ubiquitination, preventing MCL1 degradation; IRAK inhibition reduces MCL1 stability and sensitizes T-ALL to apoptosis. shRNA knockdown, pharmacological inhibitor, K63-ubiquitination assay for MCL1, xenograft model Journal of Clinical Investigation Medium 25642772
2023 IRAK1 binds to PRDX1 and prevents HECTD3 E3 ubiquitin ligase-mediated ubiquitination and degradation of PRDX1, thereby suppressing autophagic cell death and promoting radioresistance in glioma cells. Co-IP, LC-MS/MS, GST pull-down, ubiquitination assay, IRAK1 knockdown, xenograft model Cell Death & Disease Medium 37031183

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 1116 12150927
1996 IRAK: a kinase associated with the interleukin-1 receptor. Science (New York, N.Y.) 742 8599092
2002 Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 627 11923871
2000 Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nature cell biology 436 10854325
2008 Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nature immunology 346 18438411
2010 Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 315 21057262
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 232 24379360
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 175 21443627
1999 Three-dimensional structure of a complex between the death domains of Pelle and Tube. Cell 145 10589682
2008 The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1. The Biochemical journal 143 17997719
2001 Micrococci and peptidoglycan activate TLR2-->MyD88-->IRAK-->TRAF-->NIK-->IKK-->NF-kappaB signal transduction pathway that induces transcription of interleukin-8. Infection and immunity 140 11254583
2015 IRAK1 is a therapeutic target that drives breast cancer metastasis and resistance to paclitaxel. Nature communications 133 26503059
2014 IRAK signalling in cancer. British journal of cancer 132 25290089
2023 MiR146a-loaded engineered exosomes released from silk fibroin patch promote diabetic wound healing by targeting IRAK1. Signal transduction and targeted therapy 129 36775818
2011 TGF-β-induced IRAK-M expression in tumor-associated macrophages regulates lung tumor growth. Oncogene 116 21278795
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 112 30279971
2013 IRAK-M mediates Toll-like receptor/IL-1R-induced NFκB activation and cytokine production. The EMBO journal 112 23376919
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 101 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
2020 IRAK family in inflammatory autoimmune diseases. Autoimmunity reviews 79 31917263
2014 miR-146a ameliorates liver ischemia/reperfusion injury by suppressing IRAK1 and TRAF6. PloS one 79 24987958
2023 Regulation of innate immune signaling by IRAK proteins. Frontiers in immunology 76 36865541
2012 Endogenous IRAK-M attenuates postinfarction remodeling through effects on macrophages and fibroblasts. Arteriosclerosis, thrombosis, and vascular biology 76 22995519
2018 miR-146a Attenuates Sepsis-Induced Myocardial Dysfunction by Suppressing IRAK1 and TRAF6 via Targeting ErbB4 Expression. Oxidative medicine and cellular longevity 73 30224945
2003 IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction. American journal of physiology. Heart and circulatory physiology 71 12860565
2012 Augmentation of therapeutic responses in melanoma by inhibition of IRAK-1,-4. Cancer research 68 23041547
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
2010 IRAK-M regulation and function in host defense and immune homeostasis. Infectious disease reports 65 21390243
2017 Crystal structure of human IRAK1. Proceedings of the National Academy of Sciences of the United States of America 64 29208712
2015 Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies. The Journal of clinical investigation 64 25642772
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
2006 Regulation of IRAK-4 kinase activity via autophosphorylation within its activation loop. Biochemical and biophysical research communications 59 17141195
2021 SARS-CoV-2/ACE2 Interaction Suppresses IRAK-M Expression and Promotes Pro-Inflammatory Cytokine Production in Macrophages. Frontiers in immunology 56 34248968
2015 IRAK-M promotes alternative macrophage activation and fibroproliferation in bleomycin-induced lung injury. Journal of immunology (Baltimore, Md. : 1950) 52 25595781
2010 IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal). The Journal of biological chemistry 52 20400509
2023 MicroRNA-146a negatively regulates inflammation via the IRAK1/TRAF6/NF-κB signaling pathway in dry eye. Scientific reports 51 37433841
2001 The protein kinase Pelle mediates feedback regulation in the Drosophila Toll signaling pathway. Development (Cambridge, England) 49 11731453
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 48 30872404
2018 miR-146a promotes cervical cancer cell viability via targeting IRAK1 and TRAF6. Oncology reports 47 29693168
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
2003 Characterization of Pellino2, a substrate of IRAK1 and IRAK4. FEBS letters 46 12860405
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 44 37172199
2006 Differential regulation of interleukin-1 receptor associated kinase 1 (IRAK1) splice variants. Molecular immunology 44 16690127
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 40 37758100
2017 Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts. Proceedings of the National Academy of Sciences of the United States of America 40 28069966
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
2020 S100A14 suppresses metastasis of nasopharyngeal carcinoma by inhibition of NF-kB signaling through degradation of IRAK1. Oncogene 37 32555330
2020 Dexmedetomidine exerts cardioprotective effect through miR-146a-3p targeting IRAK1 and TRAF6 via inhibition of the NF-κB pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 37 33220608
2016 Epigenetic and Transcriptional Regulation of IRAK-M Expression in Macrophages. Journal of immunology (Baltimore, Md. : 1950) 37 28011933
2004 Prolonged Toll-like receptor stimulation leads to down-regulation of IRAK-4 protein. Journal of leukocyte biology 36 15258191
2019 Neutrophils Deficient in Innate Suppressor IRAK-M Enhances Anti-tumor Immune Responses. Molecular therapy : the journal of the American Society of Gene Therapy 35 31607540
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
2014 The structure function of the death domain of human IRAK-M. Cell communication and signaling : CCS 32 25481771
2002 IL-1beta-induced phosphorylation of PKB/Akt depends on the presence of IRAK-1. European journal of immunology 32 12516562
2008 Down-regulation of IRAK-4 is a component of LPS- and CpG DNA-induced tolerance in macrophages. Cellular signalling 31 18992325
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 30 37031183
2021 Targeting the IRAK1-S100A9 Axis Overcomes Resistance to Paclitaxel in Nasopharyngeal Carcinoma. Cancer research 30 33402387
2017 Immunomodulatory Molecule IRAK-M Balances Macrophage Polarization and Determines Macrophage Responses during Renal Fibrosis. Journal of immunology (Baltimore, Md. : 1950) 30 28701510
2012 Identification, characterization and the interaction of Tollip and IRAK-1 in grass carp (Ctenopharyngodon idellus). Fish & shellfish immunology 30 22659441
2007 Inherited human IRAK-4 deficiency: an update. Immunologic research 30 17917042
2021 SMARCA4 oncogenic potential via IRAK1 enhancer to activate Gankyrin and AKR1B10 in liver cancer. Oncogene 29 34140644
2018 Nod1-mediated lipolysis promotes diacylglycerol accumulation and successive inflammation via PKCδ-IRAK axis in adipocytes. Biochimica et biophysica acta. Molecular basis of disease 29 30391544
2015 Tanshinone IIA represses inflammatory response and reduces radiculopathic pain by inhibiting IRAK-1 and NF-κB/p38/JNK signaling. International immunopharmacology 29 26163178
2007 IRAK-4-dependent degradation of IRAK-1 is a negative feedback signal for TLR-mediated NF-kappaB activation. Journal of biochemistry 28 18079163
2010 IRAK-M removal counteracts dendritic cell vaccine deficits in migration and longevity. Journal of immunology (Baltimore, Md. : 1950) 27 20817880
2000 Translocation of the interleukin-1 receptor-associated kinase-1 (IRAK-1) into the nucleus. FEBS letters 26 10899313
2019 Dendritic cell exosome‑shuttled miRNA146a regulates exosome‑induced endothelial cell inflammation by inhibiting IRAK‑1: A feedback control mechanism. Molecular medicine reports 25 31638185
2014 Expression of IRAK1 in lung cancer tissues and its clinicopathological significance: a microarray study. International journal of clinical and experimental pathology 25 25550857
2015 miR-146a-5p Antagonized AGEs- and P.g-LPS-Induced ABCA1 and ABCG1 Dysregulation in Macrophages via IRAK-1 Downregulation. Inflammation 24 25805648
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 23 36765034
2022 Eliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors. Nature communications 23 35022428
2016 MicroRNA-146a Contributes to SCI Recovery via Regulating TRAF6 and IRAK1 Expression. BioMed research international 23 27830143
2021 Discovery of Highly Potent and Selective IRAK1 Degraders to Probe Scaffolding Functions of IRAK1 in ABC DLBCL. Journal of medicinal chemistry 22 34279092
2014 Variants in IRAK1-MECP2 region confer susceptibility to autoimmune thyroid diseases. Molecular and cellular endocrinology 22 25458699
2017 Critical Role of IRAK-M in Regulating Antigen-Induced Airway Inflammation. American journal of respiratory cell and molecular biology 21 28665693
2017 Inhibition of IRAK1 Ubiquitination Determines Glucocorticoid Sensitivity for TLR9-Induced Inflammation in Macrophages. Journal of immunology (Baltimore, Md. : 1950) 21 29038250
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
1999 Formation and biochemical characterization of tube/pelle death domain complexes: critical regulators of postreceptor signaling by the Drosophila toll receptor. Biochemistry 20 10512628
2023 IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies. Frontiers in immunology 19 37954584
2022 miR-146a contributes to atherosclerotic plaque stability by regulating the expression of TRAF6 and IRAK-1. Molecular biology reports 19 35195809
2019 miR-146a promotes Borna disease virus 1 replication through IRAK1/TRAF6/NF-κB signaling pathway. Virus research 19 31330207
2015 Pelle Modulates dFoxO-Mediated Cell Death in Drosophila. PLoS genetics 19 26474173
2009 CL097, a TLR7/8 ligand, inhibits TLR-4--dependent activation of IRAK-M and BCL-3 expression. Shock (Augusta, Ga.) 19 19333135
2021 Pharmacological inhibition of IRAK1 and IRAK4 prevents endothelial inflammation and atherosclerosis in ApoE-/- mice. Pharmacological research 18 34954030
2017 Micro RNA-146a But Not IRAK1 is Associated with Rheumatoid Arthritis in the Tunisian Population. Genetic testing and molecular biomarkers 18 28207326
2015 Targeting IRAK1 in T-cell acute lymphoblastic leukemia. Oncotarget 17 26068967
2011 IRAK-M in macrophages around septically and aseptically loosened hip implants. Journal of biomedical materials research. Part A 17 21987497
2017 Syk Plays a Critical Role in the Expression and Activation of IRAK1 in LPS-Treated Macrophages. Mediators of inflammation 16 28680194