IRAK4 (interleukin-1 receptor-associated kinase 4) is a cytosolic serine/threonine protein kinase of the Pelle/IRAK family and the closest human homolog of Drosophila Pelle. It has an N-terminal death domain and a C-terminal kinase domain. Upon activation of Toll-like receptors (except TLR3) and IL-1 family receptors, MyD88 death domains recruit IRAK4, which in turn recruits IRAK2 or IRAK1 to form the helical Myddosome. Clustered IRAK4 trans-autophosphorylates and phosphorylates IRAK1, IRAK2 and Pellino E3 ligases, leading to TRAF6 activation and downstream NF-kappaB, MAPK and IRF signalling and inflammatory cytokine and type I interferon production. IRAK4 also acts as a kinase-independent scaffold, for example integrating MYD88 and TRIF signals downstream of TLR4. Inherited IRAK-4 deficiency abolishes most TLR and IL-1R responses and causes susceptibility to invasive pyogenic bacterial infections in childhood.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000287 magnesium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Mg2+ is the catalytic cofactor of the IRAK4 kinase domain (UniProt COFACTOR Mg2+); the InterPro-based IEA reflects the kinase fold. Reason: Correct cofactor binding inherent to the protein kinase catalytic mechanism, but a subsidiary part of the kinase activity rather than a function in its own right. |
| GO:0002224 toll-like receptor signaling pathway | NAS PMID:38961291 Molecular definition of the endogenous Toll-like receptor si... | ACCEPT | Summary: IRAK4 is a core myddosome kinase in endogenous TLR signalling in macrophages (PMID:38961291). Reason: Well supported; IRAK4 is the apical kinase of the MyD88-dependent branch used by all TLRs except TLR3. The more specific MyD88-dependent term is also annotated. Supporting Evidence: PMID:38961291 The proteins in the myddosome core were the kinases IRAK2 and IRAK4 PMID:38961291 IRAK4 deficiencies are associated with the most comprehensive defects in TLR signalling |
| GO:0002224 toll-like receptor signaling pathway | TAS PMID:21269878 What the Myddosome structure tells us about the initiation o... | ACCEPT | Summary: Review of Myddosome structure; IRAK4 is a Myddosome component in TLR signalling. Reason: Consistent with extensive experimental evidence that IRAK4 transduces TLR signals via the Myddosome. Supporting Evidence: PMID:21269878 The recent determination of the structure of the so-called Myddosome provides us with new insights into the structural basis for innate immune signaling. PMID:20485341 Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. |
| GO:0002224 toll-like receptor signaling pathway | TAS Reactome:R-HSA-168181 | ACCEPT | Summary: Reactome TLR7/8 cascade places IRAK4 as the kinase recruited to MyD88 on activated endosomal TLRs. Reason: Consistent with human IRAK-4 deficiency abolishing TLR7/8/9 responses (PMID:16286015). Supporting Evidence: PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent Reactome:R-HSA-446694 in vitro kinase assays indicate that IRAK1 can be a direct substrate of IRAK4 |
| GO:0002446 neutrophil mediated immunity | IMP PMID:19663824 Impaired neutrophil migration and phagocytosis in IRAK-4 def... | KEEP AS NON CORE | Summary: IRAK-4 deficient patient neutrophils show impaired migration and phagocytosis (title of PMID:19663824; abstract not available in cache). Reason: Experimental IMP annotation from patient cells; the full text was not available so the curator is not overruled. The phenotype is a downstream consequence of defective TLR/IL-1R signalling in neutrophils rather than a core IRAK4 activity. |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | NAS PMID:36865541 Regulation of innate immune signaling by IRAK proteins. | ACCEPT | Summary: IRAK4 is recruited by MyD88 death domains to activated TLRs and phosphorylates IRAK1/IRAK2, initiating MyD88-dependent TLR signalling. Reason: Core process for IRAK4: it is the apical kinase and death-domain scaffold of the Myddosome (PMID:20485341, PMID:11960013). Supporting Evidence: PMID:36865541 Interactions with MyD88 allows IRAK4 to trans-autophosphorylate and recruit IRAK1. PMID:36865541 Kinase-deficient IRAK4 murine macrophages fail to produce pro-inflammatory cytokines upon stimulation of IL-1R and TLRs 2, 7, and 9 |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | TAS PMID:21269878 What the Myddosome structure tells us about the initiation o... | ACCEPT | Summary: IRAK4 is recruited by MyD88 death domains to activated TLRs and phosphorylates IRAK1/IRAK2, initiating MyD88-dependent TLR signalling. Reason: Core process for IRAK4: it is the apical kinase and death-domain scaffold of the Myddosome (PMID:20485341, PMID:11960013). Supporting Evidence: PMID:21269878 The recent determination of the structure of the so-called Myddosome provides us with new insights into the structural basis for innate immune signaling. |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | TAS Reactome:R-HSA-166058 | ACCEPT | Summary: IRAK4 is recruited by MyD88 death domains to activated TLRs and phosphorylates IRAK1/IRAK2, initiating MyD88-dependent TLR signalling. Reason: Core process for IRAK4: it is the apical kinase and death-domain scaffold of the Myddosome (PMID:20485341, PMID:11960013). Supporting Evidence: Reactome:R-HSA-166082 IRAK4 possesses a conserved N-terminal death domain (DD), which mediates interactions with MyD88 at one binding site and a downstream IRAK kinase at the other |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | TAS Reactome:R-HSA-975871 | ACCEPT | Summary: IRAK4 is recruited by MyD88 death domains to activated TLRs and phosphorylates IRAK1/IRAK2, initiating MyD88-dependent TLR signalling. Reason: Core process for IRAK4: it is the apical kinase and death-domain scaffold of the Myddosome (PMID:20485341, PMID:11960013). Supporting Evidence: Reactome:R-HSA-446694 in vitro kinase assays indicate that IRAK1 can be a direct substrate of IRAK4 |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro kinase-domain based IEA for generic protein kinase activity. Reason: Correct but less specific than established activity; IRAK4 is a Ser/Thr kinase that phosphorylates activation-loop Ser/Thr residues of IRAK1 (PMID:11960013). Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:11960013 T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4 |
| GO:0004674 protein serine/threonine kinase activity | EXP PMID:11960013 IRAK-4: a novel member of the IRAK family with the propertie... | ACCEPT | Summary: Recombinant IRAK4 phosphorylates IRAK1 and IRAK1 activation-loop peptides on T387 and S376 in vitro (PMID:11960013). Reason: Direct biochemical demonstration of Ser/Thr protein kinase activity; core molecular function. Supporting Evidence: PMID:11960013 Here we show that recombinant IRAK-1 is a substrate for IRAK-4, whereas IRAK-1 is not able to phosphorylate IRAK-4 in vitro PMID:11960013 T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4 |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: ARBA/InterPro IEA assigning EC 2.7.11.1 Ser/Thr kinase activity. Reason: Consistent with experimental data (PMID:11960013, PMID:19264966). Supporting Evidence: PMID:11960013 T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4 PMID:19264966 The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. |
| GO:0004674 protein serine/threonine kinase activity | TAS Reactome:R-HSA-166284 | ACCEPT | Summary: Reactome reactions in which IRAK4 phosphorylates IRAK1 within TLR/IL-1R complexes. Reason: Consistent with direct kinase assays (PMID:11960013). Supporting Evidence: Reactome:R-HSA-446694 in vitro kinase assays indicate that IRAK1 can be a direct substrate of IRAK4 PMID:11960013 Here we show that recombinant IRAK-1 is a substrate for IRAK-4, whereas IRAK-1 is not able to phosphorylate IRAK-4 in vitro |
| GO:0004674 protein serine/threonine kinase activity | TAS Reactome:R-HSA-446694 | ACCEPT | Summary: Reactome reactions in which IRAK4 phosphorylates IRAK1 within TLR/IL-1R complexes. Reason: Consistent with direct kinase assays (PMID:11960013). Supporting Evidence: Reactome:R-HSA-446694 in vitro kinase assays indicate that IRAK1 can be a direct substrate of IRAK4 PMID:11960013 Here we show that recombinant IRAK-1 is a substrate for IRAK-4, whereas IRAK-1 is not able to phosphorylate IRAK-4 in vitro |
| GO:0004674 protein serine/threonine kinase activity | TAS Reactome:R-HSA-975134 | ACCEPT | Summary: Reactome reactions in which IRAK4 phosphorylates IRAK1 within TLR/IL-1R complexes. Reason: Consistent with direct kinase assays (PMID:11960013). Supporting Evidence: Reactome:R-HSA-446694 in vitro kinase assays indicate that IRAK1 can be a direct substrate of IRAK4 PMID:11960013 Here we show that recombinant IRAK-1 is a substrate for IRAK-4, whereas IRAK-1 is not able to phosphorylate IRAK-4 in vitro |
| GO:0005149 interleukin-1 receptor binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer from mouse Irak4 of interleukin-1 receptor binding. Reason: IRAK4 is recruited to TIR-domain receptors indirectly, through death-domain binding to MyD88; the Myddosome assembles hierarchically from MyD88. Direct receptor binding is not the mechanism, although IRAK4 co-precipitates with receptor complexes. Supporting Evidence: PMID:20485341 Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. |
| GO:0005515 protein binding | IPI PMID:12496252 Pellino 1 is required for interleukin-1 (IL-1)-mediated sign... | REMOVE | Summary: IPI with PELI1 (PMID:12496252). Pellino 1 forms a signal-dependent complex with IRAK4, IRAK1 and TRAF6; Pellino is an IRAK4 substrate, which is captured by the Ser/Thr kinase MF. Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. Supporting Evidence: PMID:12496252 Pellino 1-IRAK-IRAK4-TRAF6 signaling complex is likely to be intermediate |
| GO:0005515 protein binding | IPI PMID:12860405 Characterization of Pellino2, a substrate of IRAK1 and IRAK4... | REMOVE | Summary: IPI with MYD88 from the Pellino2 paper (PMID:12860405, abstract only). The MyD88 death-domain interaction is captured by death domain binding from the structural papers. Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. |
| GO:0005515 protein binding | IPI PMID:12860405 Characterization of Pellino2, a substrate of IRAK1 and IRAK4... | REMOVE | Summary: IPI with PELI2 (PMID:12860405). Pellino2 is an IRAK4 substrate; the enzyme-substrate relationship is captured by the kinase MF. Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. Supporting Evidence: PMID:12860405 Pellino2 is one of the first substrates identified for IRAK1 and IRAK4. |
| GO:0005515 protein binding | IPI PMID:19264966 Identification of the phosphorylation sites on the E3 ubiqui... | REMOVE | Summary: IPI with PELI1 (PMID:19264966). Pellino 1 is phosphorylated by IRAK4; captured by the kinase MF. Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. Supporting Evidence: PMID:19264966 The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. |
| GO:0005515 protein binding | IPI PMID:20485341 Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-... | MODIFY | Summary: IPI with IRAK2 in the MyD88-IRAK4-IRAK2 death-domain crystal structure (PMID:20485341). Reason: The interaction is a homotypic death-domain interaction that assembles the Myddosome; death domain binding is the informative MF and replaces generic protein binding. Proposed replacements: death domain binding Supporting Evidence: PMID:20485341 Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. |
| GO:0005515 protein binding | IPI PMID:20485341 Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-... | MODIFY | Summary: IPI with MYD88 in the MyD88-IRAK4-IRAK2 death-domain crystal structure (PMID:20485341). Reason: The interaction is a homotypic death-domain interaction that assembles the Myddosome; death domain binding is the informative MF and replaces generic protein binding. Proposed replacements: death domain binding Supporting Evidence: PMID:20485341 Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. PMID:20485341 MyD88 DD and IRAK4 DD formed a stable complex while IRAK2 DD did not form a stable complex with either MyD88 or IRAK4 alone. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: IPI with IRAK2 from an innate immunity interaction network screen (PMID:21903422). Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: IPI with TIRAP from an innate immunity interaction network screen (PMID:21903422). Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. |
| GO:0005515 protein binding | IPI PMID:23376919 IRAK-M mediates Toll-like receptor/IL-1R-induced NFΞΊB activa... | REMOVE | Summary: IPI with mouse Irak3 (IRAK-M) (PMID:23376919). IRAK-M forms an alternative Myddosome with MyD88-IRAK4. Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. Supporting Evidence: PMID:23376919 IRAK-M was also able to interact with MyD88-IRAK-4 to form IRAK-M Myddosome |
| GO:0005515 protein binding | IPI PMID:24316379 Functional assessment of the mutational effects of human IRA... | MODIFY | Summary: IPI with MYD88 by gel filtration and NMR; IRAK4 death-domain variants R12C/R20W lose MyD88 binding (PMID:24316379). Reason: The interaction is a homotypic death-domain interaction that assembles the Myddosome; death domain binding is the informative MF and replaces generic protein binding. Proposed replacements: death domain binding Supporting Evidence: PMID:24316379 located in the death domain of IRAK4 and regarded as a SNP, caused a loss of interaction with MyD88 |
| GO:0005515 protein binding | IPI PMID:24316379 Functional assessment of the mutational effects of human IRA... | MODIFY | Summary: IPI with MYD88 isoform 1 by gel filtration and NMR; IRAK4 death-domain variants lose MyD88 binding (PMID:24316379). Reason: The interaction is a homotypic death-domain interaction that assembles the Myddosome; death domain binding is the informative MF and replaces generic protein binding. Proposed replacements: death domain binding Supporting Evidence: PMID:24316379 located in the death domain of IRAK4 and regarded as a SNP, caused a loss of interaction with MyD88 |
| GO:0005515 protein binding | IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam... | REMOVE | Summary: IPI with MYD88 from a large-scale variant cloning/interaction pipeline (PMID:25502805). Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: IPI with MYD88 from a large-scale disease-variant interaction perturbation screen (PMID:25910212). Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | REMOVE | Summary: IPI with MYD88 from a large-scale isoform interaction screen (PMID:26871637). Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: IPI with VSIG8 from the BioPlex interactome (PMID:28514442); no functional context. Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: IPI with MYD88 from a large-scale variant interaction screen (PMID:31515488). Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with PELI1 from the HuRI binary interactome (PMID:32296183). Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with ZNF597 from the HuRI binary interactome (PMID:32296183); no functional context. Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with MYD88 from the HuRI binary interactome (PMID:32296183). Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with TRIM7 from the HuRI binary interactome (PMID:32296183); no functional context. Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with IL36RN from the HuRI binary interactome (PMID:32296183); no functional context. Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. |
| GO:0005515 protein binding | IPI PMID:33238146 Dimeric Structure of the Pseudokinase IRAK3 Suggests an Allo... | REMOVE | Summary: IPI with IRAK3 pseudokinase domain by native PAGE co-migration with phosphorylated IRAK4 kinase domain (PMID:33238146). Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI with VSIG8 from a dual proteome-scale interactome (PMID:33961781); no functional context. Reason: Uninformative protein binding annotation. High-throughput or screening interaction data reported as generic protein binding. The interaction does not identify a molecular activity of IRAK4; the informative MF content (Ser/Thr kinase activity; death-domain-mediated scaffolding of the Myddosome) is captured by other annotations. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding by the protein kinase domain (InterPro IEA). Reason: IRAK4 is an active ATP-dependent protein kinase (PMID:11960013); ATP binding is required for catalysis. Supporting Evidence: PMID:11960013 Here we show that recombinant IRAK-1 is a substrate for IRAK-4, whereas IRAK-1 is not able to phosphorylate IRAK-4 in vitro |
| GO:0005576 extracellular region | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl Compara transfer from a rat Irak4 annotation of extracellular region. Reason: IRAK4 has no signal peptide or transmembrane segment and acts on the cytoplasmic side of receptor complexes and in the cytosol; an extracellular location is not supported for the human protein. Supporting Evidence: PMID:36865541 Evidence suggests that stable MyD88-containing helical complexes occur in the cytosol, and can recruit IRAK4 after stimulation file:human/IRAK4/IRAK4-deep-research-falcon.md IRAK4 is not a transmembrane, extracellular, or constitutively nuclear protein; rather, it functions specifically at sites of activated innate immune receptor signaling |
| GO:0005634 nucleus | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA (PTN000784925) transferring nuclear localization from IRAK1, IRAK3 and other Pelle-family kinases. Reason: There is no IRAK4-specific evidence for nuclear activity in the reviewed literature; UniProt records IRAK4 as cytoplasmic and all characterized IRAK4 functions occur at receptor-proximal complexes and in the cytosol. Nuclear roles reported for family members (e.g. IRAK1) appear lineage-specific rather than inherited by IRAK4. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000784925 SUPPORTS SOURCE BUT NOT TARGET Deep Pelle/IRAK/plant receptor-like kinase node; nuclear localization of some descendants (e.g. IRAK1) is not documented for IRAK4, whose characterized activity is receptor-proximal and cytosolic. UniProtKB:P51617 Β· IRAK1 SUPPORTS SOURCE BUT NOT TARGET IRAK1 nuclear localization is a family-member property not shown for IRAK4. Supporting Evidence: file:human/IRAK4/IRAK4-deep-research-falcon.md IRAK4 is not a transmembrane, extracellular, or constitutively nuclear protein; rather, it functions specifically at sites of activated innate immune receptor signaling |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA cytoplasm for the Pelle/IRAK family. Reason: Consistent with IRAK4 acting in cytosolic Myddosomes. Supporting Evidence: PMID:36865541 Evidence suggests that stable MyD88-containing helical complexes occur in the cytosol, and can recruit IRAK4 after stimulation |
| GO:0005737 cytoplasm | IC PMID:20485341 Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-... | ACCEPT | Summary: Curator inference from the Myddosome structure paper that IRAK4 is active in the cytoplasm. Reason: Myddosome assembly occurs at the cytoplasmic face of receptors and in the cytosol. Supporting Evidence: PMID:20485341 Formation of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location: cytoplasm. Reason: Consistent with all functional data. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localizes IRAK4 to the cytosol. Reason: Consistent with IRAK4 acting in cytosolic Myddosomes. |
| GO:0005829 cytosol | NAS PMID:36865541 Regulation of innate immune signaling by IRAK proteins. | ACCEPT | Summary: Review states that MyD88 helical complexes in the cytosol recruit IRAK4. Reason: Consistent with localization data. Supporting Evidence: PMID:36865541 Evidence suggests that stable MyD88-containing helical complexes occur in the cytosol, and can recruit IRAK4 after stimulation |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166082 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446634 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446648 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446684 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446692 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446694 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446701 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446862 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446868 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446894 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-450690 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-450827 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5602353 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5602603 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8948063 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-975156 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-975873 | ACCEPT | Summary: Reactome places IRAK4-containing TLR/IL-1R signalling intermediates in the cytosol. Reason: Consistent with IRAK4 localization and function. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA (PTN000701353) from Drosophila Tube and Pelle, which are recruited to the Toll receptor at the plasma membrane. Reason: IRAK4 is a peripheral protein recruited transiently to MyD88 clustered at activated plasma-membrane receptors (PMID:38961291); it is not an intrinsic membrane protein. Acceptable as a location of activity but not core. Supporting Evidence: PMID:38961291 We observed rapid formation of small MyD88 clusters at the plasma membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166082 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166091 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166119 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166284 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166286 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166362 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166363 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2262775 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2262777 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937022 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937059 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975852 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975853 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975857 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975861 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975865 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975873 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975874 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975878 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975879 | KEEP AS NON CORE | Summary: Reactome models IRAK4-containing receptor complexes (activated TLR:MyD88 or IL1R:MyD88) at the plasma membrane. Reason: IRAK4 associates with the cytoplasmic side of activated receptor complexes; the location is correct for these complexes but IRAK4 is peripheral and also acts in cytosolic Myddosomes. Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: InterPro (IRAK4 family) IEA to generic signal transduction. Reason: Correct but uninformatively general; IRAK4 acts in MyD88-dependent TLR and IL-1 receptor signalling. Proposed replacements: MyD88-dependent toll-like receptor signaling pathway Supporting Evidence: PMID:20485341 Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. |
| GO:0007249 canonical NF-kappaB signal transduction | NAS PMID:38605168 OTUD5 promotes the inflammatory immune response by enhancing... | ACCEPT | Summary: OTUD5 paper states Myddosome formation, including IRAK4 recruitment, drives NF-kB activation. Reason: IRAK4 kinase activity is required for TLR/IL-1R-induced canonical NF-kB activation (PMID:11960013); the more specific positive regulation term is also annotated. Supporting Evidence: PMID:38605168 promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-ΞΊB and MAPK signaling PMID:11960013 IRAK-4 depends on its kinase activity to activate NF-ΞΊB |
| GO:0007254 JNK cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from rat of JNK cascade. Reason: IRAK4 overexpression activates JNK-dependent reporters (PMID:11960013) and Unc5CL-induced JNK activation requires IRAK4 (PMID:22158417); IRAK4 acts upstream of the cascade via TRAF6/TAK1 rather than as a JNK-cascade kinase. Supporting Evidence: PMID:11960013 Transient overexpression of IRAK-4 activated both pathways in a dose-dependent manner PMID:22158417 Unc5CL required IRAK1, IRAK4 and TNF receptor-associated factor 6 but not MyD88 for its ability to activate these pathways. |
| GO:0008063 Toll signaling pathway | IBA GO_REF:0000033 | MODIFY | Summary: IBA (PTN000701353) from Drosophila Tube (FBgn0003882) and Pelle (FBgn0010441) to GO:0008063 Toll signaling pathway. Reason: GO:0008063 is defined by ligand binding to the Drosophila receptor Toll (activated by cleaved Spaetzle) and is not an ancestor of the vertebrate toll-like receptor signaling pathway term (GO:0002224, under pattern recognition receptor signaling). The conserved node function (death-domain kinase downstream of a TIR receptor via MyD88) is real, but for a human protein it is expressed as MyD88-dependent TLR signaling, which IRAK4 already carries with experimental support. IRAK4 is the closest human homolog of Pelle (PMID:11960013). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: LINEAGE OR TAXON MISMATCH GRANULARITY MISMATCH Sources checked: PANTHER:PTN000701353 SUPPORTS SOURCE BUT NOT TARGET Node grounded by Drosophila Tube and Pelle experimental annotations; the conserved function (death-domain kinase module downstream of a TIR receptor and MyD88) is real, but GO:0008063 is defined by the Drosophila Toll receptor and in vertebrates the equivalent is toll-like receptor signaling. FB:FBgn0010441 Β· pll SUPPORTS SOURCE BUT NOT TARGET Pelle acts in Drosophila Toll signaling; correct for the source. FB:FBgn0003882 Β· tub SUPPORTS SOURCE BUT NOT TARGET Tube acts in Drosophila Toll signaling; correct for the source. Proposed replacements: MyD88-dependent toll-like receptor signaling pathway Supporting Evidence: PMID:11960013 IRAK-4 is the closest human homolog to Pelle. PMID:20485341 Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. |
| GO:0009986 cell surface | IDA PMID:22851693 Ξ²-TrCP-mediated IRAK1 degradation releases TAK1-TRAF6 from t... | MODIFY | Summary: IDA cell surface from the beta-TrCP/IRAK1 degradation paper, which describes IRAK4 in the membrane-bound IL-1R complex I. Reason: IRAK4 is a cytosolic protein that associates with the cytoplasmic side of the IL-1 receptor complex; it is not exposed on the external cell surface. The Results section is not in the cache, so the membrane association is kept but expressed with a term for a peripheral protein on the cytoplasmic face of the plasma membrane. Proposed replacements: extrinsic component of cytoplasmic side of plasma membrane Supporting Evidence: PMID:22851693 mediates the formation of complex I (IL-1RβMyD88βIRAK4βIRAK1/2βTRAF6), where IRAK4 (IL-1 receptor-associated kinase 4) ( 12 ) is activated |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975100 | KEEP AS NON CORE | Summary: Reactome places IRAK4 in MyD88 complexes bound to activated TLR7/8/9 on endosome membranes. Reason: Endosomal TLR7/8/9 signalling is strictly IRAK4 dependent (PMID:16286015); IRAK4 is peripherally recruited to the cytoplasmic face of endosomal receptor complexes. Supporting Evidence: PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975106 | KEEP AS NON CORE | Summary: Reactome places IRAK4 in MyD88 complexes bound to activated TLR7/8/9 on endosome membranes. Reason: Endosomal TLR7/8/9 signalling is strictly IRAK4 dependent (PMID:16286015); IRAK4 is peripherally recruited to the cytoplasmic face of endosomal receptor complexes. Supporting Evidence: PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975111 | KEEP AS NON CORE | Summary: Reactome places IRAK4 in MyD88 complexes bound to activated TLR7/8/9 on endosome membranes. Reason: Endosomal TLR7/8/9 signalling is strictly IRAK4 dependent (PMID:16286015); IRAK4 is peripherally recruited to the cytoplasmic face of endosomal receptor complexes. Supporting Evidence: PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975115 | KEEP AS NON CORE | Summary: Reactome places IRAK4 in MyD88 complexes bound to activated TLR7/8/9 on endosome membranes. Reason: Endosomal TLR7/8/9 signalling is strictly IRAK4 dependent (PMID:16286015); IRAK4 is peripherally recruited to the cytoplasmic face of endosomal receptor complexes. Supporting Evidence: PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975118 | KEEP AS NON CORE | Summary: Reactome places IRAK4 in MyD88 complexes bound to activated TLR7/8/9 on endosome membranes. Reason: Endosomal TLR7/8/9 signalling is strictly IRAK4 dependent (PMID:16286015); IRAK4 is peripherally recruited to the cytoplasmic face of endosomal receptor complexes. Supporting Evidence: PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975125 | KEEP AS NON CORE | Summary: Reactome places IRAK4 in MyD88 complexes bound to activated TLR7/8/9 on endosome membranes. Reason: Endosomal TLR7/8/9 signalling is strictly IRAK4 dependent (PMID:16286015); IRAK4 is peripherally recruited to the cytoplasmic face of endosomal receptor complexes. Supporting Evidence: PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975134 | KEEP AS NON CORE | Summary: Reactome places IRAK4 in MyD88 complexes bound to activated TLR7/8/9 on endosome membranes. Reason: Endosomal TLR7/8/9 signalling is strictly IRAK4 dependent (PMID:16286015); IRAK4 is peripherally recruited to the cytoplasmic face of endosomal receptor complexes. Supporting Evidence: PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975156 | KEEP AS NON CORE | Summary: Reactome places IRAK4 in MyD88 complexes bound to activated TLR7/8/9 on endosome membranes. Reason: Endosomal TLR7/8/9 signalling is strictly IRAK4 dependent (PMID:16286015); IRAK4 is peripherally recruited to the cytoplasmic face of endosomal receptor complexes. Supporting Evidence: PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975160 | KEEP AS NON CORE | Summary: Reactome places IRAK4 in MyD88 complexes bound to activated TLR7/8/9 on endosome membranes. Reason: Endosomal TLR7/8/9 signalling is strictly IRAK4 dependent (PMID:16286015); IRAK4 is peripherally recruited to the cytoplasmic face of endosomal receptor complexes. Supporting Evidence: PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975170 | KEEP AS NON CORE | Summary: Reactome places IRAK4 in MyD88 complexes bound to activated TLR7/8/9 on endosome membranes. Reason: Endosomal TLR7/8/9 signalling is strictly IRAK4 dependent (PMID:16286015); IRAK4 is peripherally recruited to the cytoplasmic face of endosomal receptor complexes. Supporting Evidence: PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975180 | KEEP AS NON CORE | Summary: Reactome places IRAK4 in MyD88 complexes bound to activated TLR7/8/9 on endosome membranes. Reason: Endosomal TLR7/8/9 signalling is strictly IRAK4 dependent (PMID:16286015); IRAK4 is peripherally recruited to the cytoplasmic face of endosomal receptor complexes. Supporting Evidence: PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975188 | KEEP AS NON CORE | Summary: Reactome places IRAK4 in MyD88 complexes bound to activated TLR7/8/9 on endosome membranes. Reason: Endosomal TLR7/8/9 signalling is strictly IRAK4 dependent (PMID:16286015); IRAK4 is peripherally recruited to the cytoplasmic face of endosomal receptor complexes. Supporting Evidence: PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0016301 kinase activity | IDA PMID:11960013 IRAK-4: a novel member of the IRAK family with the propertie... | MODIFY | Summary: IRAK4 phosphorylates IRAK1 and IRAK1 activation-loop peptides in vitro (PMID:11960013). Reason: Correct but general; the experiment identifies Ser/Thr protein kinase activity. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:11960013 Here we show that recombinant IRAK-1 is a substrate for IRAK-4, whereas IRAK-1 is not able to phosphorylate IRAK-4 in vitro PMID:11960013 T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4 |
| GO:0019221 cytokine-mediated signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PTN000701353) cytokine-mediated signaling pathway for the IRAK family. Reason: IRAK4 is required for IL-1 family cytokine receptor signalling (IL-1, IL-18, IL-33 receptors use MyD88/IRAK4); the IBA is correctly placed. IL-1-mediated signaling is the more specific experimentally supported term. Supporting Evidence: PMID:11960013 Taken together these data indicate that IRAK-4 is indeed a component of the IL-1 signal transduction cascade. |
| GO:0019221 cytokine-mediated signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: ARBA IEA to cytokine-mediated signaling pathway. Reason: Consistent with IRAK4 function in IL-1 receptor signalling (PMID:11960013). Supporting Evidence: PMID:11960013 Taken together these data indicate that IRAK-4 is indeed a component of the IL-1 signal transduction cascade. |
| GO:0019897 extrinsic component of plasma membrane | IC PMID:20485341 Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-... | KEEP AS NON CORE | Summary: Curator inference from the Myddosome structure that IRAK4 is peripherally associated with the plasma membrane via receptor-bound MyD88. Reason: Reasonable: IRAK4 is recruited to the cytoplasmic face of activated receptors, but most signalling Myddosomes also persist in the cytosol. Supporting Evidence: PMID:20485341 Formation of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. |
| GO:0019901 protein kinase binding | IPI PMID:33238146 Dimeric Structure of the Pseudokinase IRAK3 Suggests an Allo... | KEEP AS NON CORE | Summary: Phosphorylated IRAK4 kinase domain forms a stable complex with the IRAK1 kinase domain (PMID:33238146). Reason: The interaction with IRAK1 (a kinase and IRAK4 substrate) is supported; it is more informative than generic protein binding but describes the enzyme-substrate/allosteric relationship rather than IRAK4 core activity. Supporting Evidence: PMID:33238146 However, the kinase domains of IRAK1 and IRAK4-P did co-migrate, indicating the formation of a stable complex |
| GO:0031663 lipopolysaccharide-mediated signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IBA to lipopolysaccharide-mediated signaling pathway. Reason: IRAK4 is required for TLR4 (LPS) signalling through both MYD88 and TRIF branches (PMID:35977521). Supporting Evidence: PMID:35977521 confirmed that the kinase activity of IRAK4 is essential for MYD88 signaling PMID:35977521 IRAK4 scaffold is, therefore, essential in integrating MYD88 and TRIF in TLR4 signaling. |
| GO:0034142 toll-like receptor 4 signaling pathway | IC PMID:35977521 The IRAK4 scaffold integrates TLR4-driven TRIF and MYD88 sig... | ACCEPT | Summary: IRAK4 kinase and scaffold roles in TLR4 signalling (PMID:35977521). Reason: Direct experimental data in the source paper; the IRAK4 scaffold integrates MYD88 and TRIF signalling downstream of TLR4. Supporting Evidence: PMID:35977521 confirmed that the kinase activity of IRAK4 is essential for MYD88 signaling PMID:35977521 IRAK4 scaffold is, therefore, essential in integrating MYD88 and TRIF in TLR4 signaling. |
| GO:0034162 toll-like receptor 9 signaling pathway | IMP PMID:16286015 Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/be... | ACCEPT | Summary: IRAK-4-deficient patient cells fail to induce IFN-alpha/beta and -lambda in response to TLR7, TLR8 and TLR9 agonists (PMID:16286015). Reason: Human loss-of-function evidence; IRAK4 is the Myddosome kinase in the TLR9 pathway. Supporting Evidence: PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0034162 toll-like receptor 9 signaling pathway | TAS Reactome:R-HSA-168138 | ACCEPT | Summary: Reactome TLR9 cascade. Reason: Consistent with IMP data (PMID:16286015). Supporting Evidence: PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0035556 intracellular signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: IBA intracellular signal transduction for Pelle/IRAK-family kinases. Reason: Correct, if general; IRAK4 is an intracellular signalling kinase. Supporting Evidence: PMID:11960013 IRAK-4 depends on its kinase activity to activate NF-ΞΊB |
| GO:0038172 interleukin-33-mediated signaling pathway | IDA PMID:11960013 IRAK-4: a novel member of the IRAK family with the propertie... | MODIFY | Summary: IDA to interleukin-33-mediated signaling pathway from the IRAK-4 discovery paper. Reason: The full text of PMID:11960013 studies IL-1 signalling in 293RI cells (IL-1RI expressing) and does not mention IL-33 or its receptor ST2/IL1RL1; the experiments support IL-1-mediated signaling. IRAK4 very likely also acts in IL-33 signalling (IL1RL1 uses MyD88), but that is not shown in this paper. Proposed replacements: interleukin-1-mediated signaling pathway Supporting Evidence: PMID:11960013 Both IRAK-1 and TRAF6 associate with endogenous IRAK-4 in a rapid, transient, and IL-1-dependent manner PMID:11960013 Taken together these data indicate that IRAK-4 is indeed a component of the IL-1 signal transduction cascade. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PTN008405164) positive regulation of canonical NF-kappaB signal transduction. Reason: IRAK4 kinase activity is required for IL-1/TLR-induced NF-kB activation (PMID:11960013). Supporting Evidence: PMID:11960013 IRAK-4 depends on its kinase activity to activate NF-ΞΊB |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IMP PMID:22158417 The death domain-containing protein Unc5CL is a novel MyD88-... | ACCEPT | Summary: Unc5CL-induced NF-kB activation requires IRAK4 (PMID:22158417). Reason: Experimental support in a MyD88-independent context; consistent with the core IRAK4 role in NF-kB activation. Supporting Evidence: PMID:22158417 Unc5CL required IRAK1, IRAK4 and TNF receptor-associated factor 6 but not MyD88 for its ability to activate these pathways. |
| GO:0043405 regulation of MAP kinase activity | NAS PMID:38605168 OTUD5 promotes the inflammatory immune response by enhancing... | KEEP AS NON CORE | Summary: OTUD5 paper states Myddosome formation promotes MAPK signalling. Reason: IRAK4 acts upstream of MAPK activation via TRAF6/TAK1; a regulatory role, not core. Supporting Evidence: PMID:38605168 promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-ΞΊB and MAPK signaling |
| GO:0044546 NLRP3 inflammasome complex assembly | NAS PMID:36865541 Regulation of innate immune signaling by IRAK proteins. | MODIFY | Summary: Review notes a role for IRAK4 and IRAK1 in non-transcriptional priming of the NLRP3 inflammasome. Reason: IRAK4 is not a component that assembles the inflammasome; it acts upstream in priming. A positive regulation term represents this correctly. Proposed replacements: positive regulation of NLRP3 inflammasome complex assembly Supporting Evidence: PMID:36865541 study of non-transcriptional priming of the NLRP3 inflammasome revealed an additional role for IRAK4 and IRAK1 |
| GO:0045087 innate immune response | TAS PMID:21269878 What the Myddosome structure tells us about the initiation o... | ACCEPT | Summary: IRAK4 is required for TLR/IL-1R-driven innate immunity. Reason: Human IRAK-4 deficiency causes susceptibility to invasive pyogenic bacterial infection (UniProt IMD67) and loss of TLR responses (PMID:16286015). Supporting Evidence: PMID:21269878 The recent determination of the structure of the so-called Myddosome provides us with new insights into the structural basis for innate immune signaling. PMID:16286015 The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0048661 positive regulation of smooth muscle cell proliferation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of smooth muscle cell proliferation (IEA), transferred from rat Irak4, from a study of IL-18-induced CXCL16 expression in aortic smooth muscle cells (PMID:15890643). Reason: The row is transferred from rat Irak4, annotated from a mutant phenotype in a study of interleukin-18 signalling in aortic smooth muscle cells, where IL-18 induces the chemokine CXCL16, which promotes smooth muscle cell proliferation, through MyD88, IRAK and TRAF6 (PMID:15890643). The claim therefore has an experimental basis. IRAK4 acts here as a signalling kinase downstream of the IL-18 receptor, and proliferation is a consequence of the cytokine response in one cell type rather than a process in which IRAK4 itself takes part. The term over-reads the pathway output and is marked as an over-annotation rather than removed. |
| GO:0070498 interleukin-1-mediated signaling pathway | IDA PMID:20485341 Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-... | ACCEPT | Summary: Myddosome structure (MyD88-IRAK4-IRAK2) in TLR/IL-1R signalling (PMID:20485341). Reason: IRAK4 is a core IL-1R signalling kinase (PMID:11960013). Supporting Evidence: PMID:20485341 Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. PMID:11960013 Both IRAK-1 and TRAF6 associate with endogenous IRAK-4 in a rapid, transient, and IL-1-dependent manner |
| GO:0070498 interleukin-1-mediated signaling pathway | NAS PMID:36865541 Regulation of innate immune signaling by IRAK proteins. | ACCEPT | Summary: Review of IRAK roles in IL-1R and TLR signalling. Reason: Consistent with primary data. Supporting Evidence: PMID:36865541 Kinase-deficient IRAK4 murine macrophages fail to produce pro-inflammatory cytokines upon stimulation of IL-1R and TLRs 2, 7, and 9 |
| GO:0070498 interleukin-1-mediated signaling pathway | TAS Reactome:R-HSA-9020702 | ACCEPT | Summary: Reactome IL-1 signalling. Reason: Consistent with primary data (PMID:11960013). Supporting Evidence: PMID:11960013 Both IRAK-1 and TRAF6 associate with endogenous IRAK-4 in a rapid, transient, and IL-1-dependent manner |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea-based IEA (RHEA:17989, L-seryl-protein phosphorylation). Reason: IRAK4 phosphorylates Ser residues (e.g. IRAK1 S376) (PMID:11960013). Supporting Evidence: PMID:11960013 T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4 |
| GO:1902554 serine/threonine protein kinase complex | NAS PMID:30256449 Understanding early TLR signaling through the Myddosome. | ACCEPT | Summary: Myddosome review: IRAK4 is part of the Myddosome, an oligomeric complex of MyD88 and IRAK kinases. Reason: The Myddosome (MyD88-IRAK4-IRAK2/IRAK1) is a Ser/Thr kinase-containing complex; GO has no Myddosome-specific term, so this is the best available complex term. Supporting Evidence: PMID:30256449 Upon activation, TLRs facilitate the assembly of large intracellular oligomeric signaling complexes, termed Myddosomes PMID:20485341 Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. |
| GO:1990266 neutrophil migration | IMP PMID:19663824 Impaired neutrophil migration and phagocytosis in IRAK-4 def... | KEEP AS NON CORE | Summary: IRAK-4 deficient patient neutrophils show impaired migration (title of PMID:19663824; abstract not available in cache). Reason: Experimental IMP from patient cells that the curator read in full; retained, but the defect is a downstream consequence of absent TLR/IL-1R signalling rather than a direct IRAK4 function in the migration machinery. |
| GO:0035591 signaling adaptor activity | IDA PMID:35977521 The IRAK4 scaffold integrates TLR4-driven TRIF and MYD88 sig... | NEW | Summary: IRAK4 bridges MyD88 and IRAK1/IRAK2 through its death domain and acts as a kinase-independent scaffold for TRAF6 activation downstream of MYD88 and TRIF in TLR4 signalling. Reason: The scaffold (adaptor) function of IRAK4 is separable from its kinase activity and is supported by structural (PMID:20485341) and genetic (PMID:35977521) evidence; no existing MF annotation captures it other than generic protein binding. Supporting Evidence: PMID:35977521 IRAK4 scaffold is, therefore, essential in integrating MYD88 and TRIF in TLR4 signaling. PMID:20485341 Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. |
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Download this section (compressed HTML)Q: Which IRAK4 outputs in human myeloid cells require its kinase activity and which require only its scaffold function, given that IRAK4 kinase inhibition in human macrophages spares most cytokine production but impairs IRF5 activation?
Q: Should GO provide a cellular component term for the Myddosome (MyD88-IRAK4-IRAK2/IRAK1 helical death-domain assembly), rather than the generic serine/threonine protein kinase complex?
Q: Does IRAK4 act directly in IL-33 (IL1RL1) and IL-18 receptor signalling in human cells, and is there primary evidence suitable for pathway-specific annotation?
Q: Should PAINT node PTN000701353 carry GO:0008063 Toll signaling pathway at a level that propagates to vertebrate IRAKs, given that GO:0008063 is defined by the Drosophila Toll receptor and is not an ancestor of the toll-like receptor signaling pathway term?
Q: Which IRAK1 residues does IRAK4 phosphorylate directly in cells (the in vitro peptide data implicate T387/S376, whereas later work places the initiating IRAK4 event at IRAK1 T209 and assigns T387 partly to IRAK1 autophosphorylation), and does the reported MyD88-independent IRAK4-IRAK1 activation after DNA double-strand breaks warrant annotation once confirmed?
Experiment: Compare kinase-dead (D311N or K213/214A) and IRAK4-null human primary macrophages across TLR1/2, TLR4, TLR5, TLR7/8 and IL-1R stimuli with phosphoproteomics to separate kinase from scaffold outputs.
Experiment: Test IRAK4 recruitment and requirement in IL-33 and IL-18 signalling in IRAK4-deficient patient cells complemented with wild-type or kinase-dead IRAK4.
Experiment: Map in vivo IRAK4 substrates in human cells using analog-sensitive IRAK4 and thiophosphate labelling.
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