IRAK3 (IRAK-M) is a member of the IL-1 receptor-associated kinase family composed of an N-terminal death domain, a central pseudokinase domain and a C-terminal region with a TRAF6-binding motif. Unlike IRAK1 and IRAK4 it lacks the catalytic HRD aspartate (replaced by CGS) and an intact Mg-binding DFG motif, binds ATP only weakly and has no established kinase activity. Expressed mainly in monocytes, macrophages, dendritic cells and lung epithelium and induced by Toll-like receptor stimulation, IRAK3 is incorporated into MyD88-IRAK4 receptor-proximal complexes, where it retains IRAK1 and IRAK4 on MyD88, blocks IRAK1-TRAF6 coupling and redirects signaling to a MEKK3-dependent second wave of NF-kB that induces inhibitory genes. The net effect is negative feedback on TLR and IL-1 receptor signaling, limiting cytokine production by macrophages and contributing to endotoxin tolerance. Its pseudokinase domain forms a head-to-head homodimer and transiently engages phosphorylated IRAK4. In IL-33-stimulated dendritic cells, PIN1 isomerisation of phospho-Ser110 IRAK3 promotes its nuclear translocation and induction of selected inflammatory genes. IRAK3 is primarily cytoplasmic. Variants are associated with early-onset persistent asthma.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000287 magnesium ion binding | IDA PMID:10383454 IRAK-M is a novel member of the Pelle/interleukin-1 receptor... | REMOVE | Summary: Human IRAK3 lacks the Mg2+-coordinating DFG motif (replaced by DFA) and recombinant pseudokinase domain shows no thermal shift with MgCl2 or Mg-ATP. Reason: Magnesium ion binding in kinases is a property of the catalytic Mg-ATP complex. The IRAK3 structure paper shows the DFG motif is altered to DFA, the catalytic HRD is replaced by CGS, and MgCl2 or MgCl2 plus ATP produced no thermal stabilisation of the IRAK3 pseudokinase domain, whereas IRAK2 was stabilised. The 1999 report itself describes only negligible autophosphorylation. This is a directly contradicted claim rather than an absence of evidence, so the term is removed for both the IDA and the ARBA/Compara-derived IEA row. Supporting Evidence: PMID:33238146 The canonical catalytic βHRDβ-motif is missing entirely in IRAK3 and replaced with βCGS,β whereas the Mg2+-coordinating βDFGβ-motif is slightly altered to βDFA.β PMID:33238146 In agreement with the structure-guided predictions, MgCl2 and ATP did not induce significant thermal shifts in IRAK3, while the addition of staurosporine resulted in a +7.9Β°C shift of the melting temperature. PMID:10383454 Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. |
| GO:0000287 magnesium ion binding | IEA GO_REF:0000120 | REMOVE | Summary: Human IRAK3 lacks the Mg2+-coordinating DFG motif (replaced by DFA) and recombinant pseudokinase domain shows no thermal shift with MgCl2 or Mg-ATP. Reason: Magnesium ion binding in kinases is a property of the catalytic Mg-ATP complex. The IRAK3 structure paper shows the DFG motif is altered to DFA, the catalytic HRD is replaced by CGS, and MgCl2 or MgCl2 plus ATP produced no thermal stabilisation of the IRAK3 pseudokinase domain, whereas IRAK2 was stabilised. The 1999 report itself describes only negligible autophosphorylation. This is a directly contradicted claim rather than an absence of evidence, so the term is removed for both the IDA and the ARBA/Compara-derived IEA row. Supporting Evidence: PMID:33238146 The canonical catalytic βHRDβ-motif is missing entirely in IRAK3 and replaced with βCGS,β whereas the Mg2+-coordinating βDFGβ-motif is slightly altered to βDFA.β PMID:33238146 In agreement with the structure-guided predictions, MgCl2 and ATP did not induce significant thermal shifts in IRAK3, while the addition of staurosporine resulted in a +7.9Β°C shift of the melting temperature. |
| GO:0001819 positive regulation of cytokine production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Context-specific positive effect on cytokine expression, transferred from mouse Irak3 by Ensembl Compara. Reason: The predominant physiological role of IRAK3 is to restrain TLR/IL-1R-induced cytokine production, but in IL-33-stimulated dendritic cells PIN1-isomerised IRAK3 translocates to the nucleus and is required for induction of selected proinflammatory genes, and the IRAK-M myddosome drives a second wave of NF-kB activation. A positive effect on cytokine production therefore holds in a restricted context and is kept as non-core. Supporting Evidence: PMID:29686383 Upon IL-33-induced airway inflammation, PIN1 is activated for binding with and isomerization of IRAK-M, resulting in IRAK-M nuclear translocation and induction of selected proinflammatory genes in dendritic cells. PMID:29686383 Here we show that interleukin receptor associated kinase M (IRAK-M) is a PIN1 target critical for IL-33 signaling in allergic asthma. |
| GO:0001960 negative regulation of cytokine-mediated signaling pathway | IC PMID:12150927 IRAK-M is a negative regulator of Toll-like receptor signali... | MODIFY | Summary: IRAK3 restrains IL-1 receptor signaling; the general cytokine-mediated term can be refined to IL-1-mediated signaling. Reason: Kobayashi et al. showed increased cytokine production upon IL-1 as well as TLR stimulation in IRAK-M-deficient cells, and IRAK3 acts at the MyD88-IRAK4 receptor-proximal complex shared by IL-1R and TLRs. The supported specific claim is negative regulation of interleukin-1-mediated signaling pathway (GO:2000660), a descendant of the annotated term; the IL-1 pathway itself is already annotated to the gene. The broader term is not wrong. Proposed replacements: negative regulation of interleukin-1-mediated signaling pathway Supporting Evidence: PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. PMID:12150927 IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. |
| GO:0001960 negative regulation of cytokine-mediated signaling pathway | IEA GO_REF:0000117 | MODIFY | Summary: IRAK3 restrains IL-1 receptor signaling; the general cytokine-mediated term can be refined to IL-1-mediated signaling. Reason: Kobayashi et al. showed increased cytokine production upon IL-1 as well as TLR stimulation in IRAK-M-deficient cells, and IRAK3 acts at the MyD88-IRAK4 receptor-proximal complex shared by IL-1R and TLRs. The supported specific claim is negative regulation of interleukin-1-mediated signaling pathway (GO:2000660), a descendant of the annotated term; the IL-1 pathway itself is already annotated to the gene. The broader term is not wrong. Proposed replacements: negative regulation of interleukin-1-mediated signaling pathway Supporting Evidence: PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. PMID:12150927 IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. |
| GO:0002684 positive regulation of immune system process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA prediction of positive regulation of immune system process contradicts the dominant inhibitory role of IRAK3. Reason: IRAK3 is principally a negative feedback regulator of TLR/IL-1R signaling (reduced endotoxin tolerance and increased inflammatory responses in knockouts). A positive role is restricted to specialised settings such as IL-33/PIN1 signaling in dendritic cells. A broad unqualified positive regulation of immune system process term misrepresents the gene, so it is marked as over-annotated rather than kept. Supporting Evidence: PMID:12150927 We show here that IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling. PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. PMID:29686383 Here we show that interleukin receptor associated kinase M (IRAK-M) is a PIN1 target critical for IL-33 signaling in allergic asthma. |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | TAS PMID:10383454 IRAK-M is a novel member of the Pelle/interleukin-1 receptor... | ACCEPT | Summary: IRAK3 acts within MyD88-dependent TLR signaling as a component of the MyD88-IRAK4 receptor complex. Reason: IRAK3 is induced by TLR stimulation, binds the MyD88-IRAK4 complex through its death domain (Trp74 surface), forms an IRAK-M myddosome that drives MEKK3-dependent second-wave NF-kB activation, and prevents release of IRAK1/IRAK4 from MyD88. It therefore does part of the work of the MyD88-dependent pathway (as a feedback component), which justifies participation. The original 1999 paper showed IRAK-M reconstitutes IL-1 responses and that IRAK family members are required for LPS signal transduction. Supporting Evidence: PMID:12150927 IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. PMID:38268724 Surface 1, with central residue Trp74, binds to MyD88/IRAK-4. PMID:23376919 IRAK-M was also able to interact with MyD88-IRAK-4 to form IRAK-M Myddosome to mediate TLR7-induced MEKK3-dependent second wave NFΞΊB activation PMID:10383454 In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000107 | REMOVE | Summary: IRAK3 is a pseudokinase: the catalytic HRD aspartate is replaced (CGS, Ser-293), Mg-binding DFG is DFA, and only negligible autophosphorylation was reported. Reason: Protein kinase activity requires a catalytic aspartate that IRAK3 lacks (HRD replaced by CGS), and this substitution is conserved across 134 vertebrate IRAK3 orthologues. The discovery paper reports only negligible autophosphorylation, the structure paper describes IRAK3 as a pseudokinase lacking catalytic activity, and no physiological phosphorylation substrate has been identified. UniProt flags the active-site substitution in a curated CAUTION. The kinase-domain fold is used for protein interaction (head-to-head homodimer, transient complex with phosphorylated IRAK4), not phosphotransfer. Transfer of protein kinase activity from the catalytically active IRAK1/IRAK4 subfamilies is not justified for the IRAK3 subfamily (PTHR24419:SF7). Removed for all rows of this claim. Supporting Evidence: PMID:33238146 In contrast to the active kinases IRAK1 and IRAK4, IRAK2 and IRAK3 are pseudokinases lacking catalytic activity and their functions are poorly understood. PMID:33238146 The canonical catalytic βHRDβ-motif is missing entirely in IRAK3 and replaced with βCGS,β whereas the Mg2+-coordinating βDFGβ-motif is slightly altered to βDFA.β file:human/IRAK3/IRAK3-uniprot.txt Ser-293 is present instead of the conserved Asp which is expected to be an active site residue. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:10383454 IRAK-M is a novel member of the Pelle/interleukin-1 receptor... | REMOVE | Summary: IRAK3 is a pseudokinase: the catalytic HRD aspartate is replaced (CGS, Ser-293), Mg-binding DFG is DFA, and only negligible autophosphorylation was reported. Reason: Protein kinase activity requires a catalytic aspartate that IRAK3 lacks (HRD replaced by CGS), and this substitution is conserved across 134 vertebrate IRAK3 orthologues. The discovery paper reports only negligible autophosphorylation, the structure paper describes IRAK3 as a pseudokinase lacking catalytic activity, and no physiological phosphorylation substrate has been identified. UniProt flags the active-site substitution in a curated CAUTION. The kinase-domain fold is used for protein interaction (head-to-head homodimer, transient complex with phosphorylated IRAK4), not phosphotransfer. Transfer of protein kinase activity from the catalytically active IRAK1/IRAK4 subfamilies is not justified for the IRAK3 subfamily (PTHR24419:SF7). Removed for all rows of this claim. Although this row is experimental, the cached abstract of the cited paper itself reports only negligible autophosphorylation, and later structural/biochemical work contradicts catalytic competence. Supporting Evidence: PMID:10383454 Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. PMID:33238146 In contrast to the active kinases IRAK1 and IRAK4, IRAK2 and IRAK3 are pseudokinases lacking catalytic activity and their functions are poorly understood. PMID:33238146 The canonical catalytic βHRDβ-motif is missing entirely in IRAK3 and replaced with βCGS,β whereas the Mg2+-coordinating βDFGβ-motif is slightly altered to βDFA.β file:human/IRAK3/IRAK3-uniprot.txt Ser-293 is present instead of the conserved Asp which is expected to be an active site residue. |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | REMOVE | Summary: IRAK3 is a pseudokinase: the catalytic HRD aspartate is replaced (CGS, Ser-293), Mg-binding DFG is DFA, and only negligible autophosphorylation was reported. Reason: Protein kinase activity requires a catalytic aspartate that IRAK3 lacks (HRD replaced by CGS), and this substitution is conserved across 134 vertebrate IRAK3 orthologues. The discovery paper reports only negligible autophosphorylation, the structure paper describes IRAK3 as a pseudokinase lacking catalytic activity, and no physiological phosphorylation substrate has been identified. UniProt flags the active-site substitution in a curated CAUTION. The kinase-domain fold is used for protein interaction (head-to-head homodimer, transient complex with phosphorylated IRAK4), not phosphotransfer. Transfer of protein kinase activity from the catalytically active IRAK1/IRAK4 subfamilies is not justified for the IRAK3 subfamily (PTHR24419:SF7). Removed for all rows of this claim. Supporting Evidence: PMID:33238146 In contrast to the active kinases IRAK1 and IRAK4, IRAK2 and IRAK3 are pseudokinases lacking catalytic activity and their functions are poorly understood. PMID:33238146 The canonical catalytic βHRDβ-motif is missing entirely in IRAK3 and replaced with βCGS,β whereas the Mg2+-coordinating βDFGβ-motif is slightly altered to βDFA.β file:human/IRAK3/IRAK3-uniprot.txt Ser-293 is present instead of the conserved Asp which is expected to be an active site residue. |
| GO:0005515 protein binding | IPI PMID:29686383 The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity i... | REMOVE | Summary: PIN1 binds IRAK3 phosphorylated at Ser-110 after IL-33 stimulation; IRAK3 is the substrate of PIN1 prolyl isomerisation. Reason: The interaction is real and functionally important (PIN1 isomerises pSer110-Pro111 of IRAK3, promoting its nuclear translocation), but bare protein binding conveys no function for IRAK3. IRAK3 is the substrate here; the activity belongs to PIN1, and no informative IRAK3 MF term describes being a PIN1 substrate. Removed per the protein-binding policy; removal does not dispute the interaction. Supporting Evidence: PMID:29686383 Upon IL-33-induced airway inflammation, PIN1 is activated for binding with and isomerization of IRAK-M, resulting in IRAK-M nuclear translocation and induction of selected proinflammatory genes in dendritic cells. PMID:29686383 Here we show that interleukin receptor associated kinase M (IRAK-M) is a PIN1 target critical for IL-33 signaling in allergic asthma. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: HuRI binary Y2H interaction with TRAF6, an E3 ubiquitin ligase; IRAK3 carries a TRAF6-binding motif in its C-terminal region. Reason: Bare protein binding is uninformative. TRAF6 is a RING E3 ubiquitin ligase, and independent mutagenesis maps a TRAF6 binding motif at P478 of IRAK3 and an Arg97 death-domain surface important for TRAF6 association. The interaction is better captured as ubiquitin protein ligase binding (GO:0031625). Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:25481771 IL-8 protein expression was dependent on R97 and the TRAF6 binding motif at P478. PMID:38268724 Arg97 was also found to be pivotal for IRAK-M's interaction with IRAK-1, and important for IRAK-M's interaction with TRAF6. |
| GO:0005524 ATP binding | IDA PMID:10383454 IRAK-M is a novel member of the Pelle/interleukin-1 receptor... | KEEP AS NON CORE | Summary: IRAK3 binds ATP only weakly (Kd about 196 uM) and Mg-independently; the pocket may be nucleotide-occupied at cellular ATP levels. Reason: Thermal shift and isothermal analyses show weak ATP binding (estimated Kd 196 uM), with the authors concluding the pocket may be nucleotide-bound at cellular millimolar ATP; UniProt records low-affinity ATP binding from this work. ATP binding is therefore supported but is not catalytic and not the core function, so it is kept as non-core. Supporting Evidence: PMID:33238146 while IRAK3 is a weak ATP-binder with an estimated Kd of 196 Β± 19 ΞΌM at 45Β°C PMID:33238146 Collectively, our results therefore suggest that the ATP-binding pocket of IRAK3 may be nucleotide-bound at cellular ATP concentrations. file:human/IRAK3/IRAK3-uniprot.txt The nucleotide binding domain binds ATP with low affinity. |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IRAK3 binds ATP only weakly (Kd about 196 uM) and Mg-independently; the pocket may be nucleotide-occupied at cellular ATP levels. Reason: Thermal shift and isothermal analyses show weak ATP binding (estimated Kd 196 uM), with the authors concluding the pocket may be nucleotide-bound at cellular millimolar ATP; UniProt records low-affinity ATP binding from this work. ATP binding is therefore supported but is not catalytic and not the core function, so it is kept as non-core. Supporting Evidence: PMID:33238146 while IRAK3 is a weak ATP-binder with an estimated Kd of 196 Β± 19 ΞΌM at 45Β°C PMID:33238146 Collectively, our results therefore suggest that the ATP-binding pocket of IRAK3 may be nucleotide-bound at cellular ATP concentrations. file:human/IRAK3/IRAK3-uniprot.txt The nucleotide binding domain binds ATP with low affinity. |
| GO:0005634 nucleus | EXP PMID:29686383 The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity i... | KEEP AS NON CORE | Summary: IRAK3 is detected in the nucleus in resting cells and translocates there on IL-33/PIN1 signaling. Reason: IRAK3 is present in both cytoplasm and nucleus in resting cells and becomes exclusively cytoplasmic after Pam3CSK4, while IL-33 stimulation drives PIN1-dependent nuclear translocation in dendritic cells. Nuclear localisation is a stimulus-specific mode rather than the main site of action at receptor-proximal complexes, so it is kept as non-core. The IBA (PTN000784925) is a deep kinase node; it agrees with the direct observations. Supporting Evidence: PMID:29686383 Upon IL-33-induced airway inflammation, PIN1 is activated for binding with and isomerization of IRAK-M, resulting in IRAK-M nuclear translocation and induction of selected proinflammatory genes in dendritic cells. PMID:17379480 IRAK-M is ubiquitously present in the cell, and becomes exclusively cytoplasmic upon bacterial lipoprotein Pam(3)CSK(4) challenge. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IRAK3 is detected in the nucleus in resting cells and translocates there on IL-33/PIN1 signaling. Reason: IRAK3 is present in both cytoplasm and nucleus in resting cells and becomes exclusively cytoplasmic after Pam3CSK4, while IL-33 stimulation drives PIN1-dependent nuclear translocation in dendritic cells. Nuclear localisation is a stimulus-specific mode rather than the main site of action at receptor-proximal complexes, so it is kept as non-core. The IBA (PTN000784925) is a deep kinase node; it agrees with the direct observations. Supporting Evidence: PMID:29686383 Upon IL-33-induced airway inflammation, PIN1 is activated for binding with and isomerization of IRAK-M, resulting in IRAK-M nuclear translocation and induction of selected proinflammatory genes in dendritic cells. PMID:17379480 IRAK-M is ubiquitously present in the cell, and becomes exclusively cytoplasmic upon bacterial lipoprotein Pam(3)CSK(4) challenge. |
| GO:0005634 nucleus | IDA PMID:17379480 Differential regulation and role of interleukin-1 receptor a... | KEEP AS NON CORE | Summary: IRAK3 is detected in the nucleus in resting cells and translocates there on IL-33/PIN1 signaling. Reason: IRAK3 is present in both cytoplasm and nucleus in resting cells and becomes exclusively cytoplasmic after Pam3CSK4, while IL-33 stimulation drives PIN1-dependent nuclear translocation in dendritic cells. Nuclear localisation is a stimulus-specific mode rather than the main site of action at receptor-proximal complexes, so it is kept as non-core. The IBA (PTN000784925) is a deep kinase node; it agrees with the direct observations. Supporting Evidence: PMID:29686383 Upon IL-33-induced airway inflammation, PIN1 is activated for binding with and isomerization of IRAK-M, resulting in IRAK-M nuclear translocation and induction of selected proinflammatory genes in dendritic cells. PMID:17379480 IRAK-M is ubiquitously present in the cell, and becomes exclusively cytoplasmic upon bacterial lipoprotein Pam(3)CSK(4) challenge. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IRAK3 is detected in the nucleus in resting cells and translocates there on IL-33/PIN1 signaling. Reason: IRAK3 is present in both cytoplasm and nucleus in resting cells and becomes exclusively cytoplasmic after Pam3CSK4, while IL-33 stimulation drives PIN1-dependent nuclear translocation in dendritic cells. Nuclear localisation is a stimulus-specific mode rather than the main site of action at receptor-proximal complexes, so it is kept as non-core. The IBA (PTN000784925) is a deep kinase node; it agrees with the direct observations. Supporting Evidence: PMID:29686383 Upon IL-33-induced airway inflammation, PIN1 is activated for binding with and isomerization of IRAK-M, resulting in IRAK-M nuclear translocation and induction of selected proinflammatory genes in dendritic cells. PMID:17379480 IRAK-M is ubiquitously present in the cell, and becomes exclusively cytoplasmic upon bacterial lipoprotein Pam(3)CSK(4) challenge. |
| GO:0005737 cytoplasm | EXP PMID:29686383 The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity i... | ACCEPT | Summary: IRAK3 is a cytoplasmic signaling protein acting at MyD88-IRAK4 complexes. Reason: IRAK3 is an intracellular signaling protein that acts on cytoplasmic MyD88-IRAK4 receptor-proximal complexes; after Pam3CSK4 challenge it becomes exclusively cytoplasmic. Cytoplasm is the principal site of its function. Supporting Evidence: PMID:17379480 IRAK-M is ubiquitously present in the cell, and becomes exclusively cytoplasmic upon bacterial lipoprotein Pam(3)CSK(4) challenge. PMID:12150927 IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IRAK3 is a cytoplasmic signaling protein acting at MyD88-IRAK4 complexes. Reason: IRAK3 is an intracellular signaling protein that acts on cytoplasmic MyD88-IRAK4 receptor-proximal complexes; after Pam3CSK4 challenge it becomes exclusively cytoplasmic. Cytoplasm is the principal site of its function. Supporting Evidence: PMID:17379480 IRAK-M is ubiquitously present in the cell, and becomes exclusively cytoplasmic upon bacterial lipoprotein Pam(3)CSK(4) challenge. PMID:12150927 IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. |
| GO:0005737 cytoplasm | IDA PMID:17379480 Differential regulation and role of interleukin-1 receptor a... | ACCEPT | Summary: IRAK3 is a cytoplasmic signaling protein acting at MyD88-IRAK4 complexes. Reason: IRAK3 is an intracellular signaling protein that acts on cytoplasmic MyD88-IRAK4 receptor-proximal complexes; after Pam3CSK4 challenge it becomes exclusively cytoplasmic. Cytoplasm is the principal site of its function. Supporting Evidence: PMID:17379480 IRAK-M is ubiquitously present in the cell, and becomes exclusively cytoplasmic upon bacterial lipoprotein Pam(3)CSK(4) challenge. PMID:12150927 IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: IRAK3 is a cytoplasmic signaling protein acting at MyD88-IRAK4 complexes. Reason: IRAK3 is an intracellular signaling protein that acts on cytoplasmic MyD88-IRAK4 receptor-proximal complexes; after Pam3CSK4 challenge it becomes exclusively cytoplasmic. Cytoplasm is the principal site of its function. Supporting Evidence: PMID:17379480 IRAK-M is ubiquitously present in the cell, and becomes exclusively cytoplasmic upon bacterial lipoprotein Pam(3)CSK(4) challenge. PMID:12150927 IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from the Pelle/Tube node; IRAK3 is recruited by death-domain interaction to receptor-proximal MyD88 complexes at the cytoplasmic face of the membrane. Reason: The PAINT node PTN000701353 (IRAK/Pelle clade, which includes IRAK3) was seeded by Drosophila Pelle and Tube, which are recruited to the membrane-bound Toll receptor complex. IRAK3 is inside that clade and binds MyD88-IRAK4 through its death domain, so transient association with receptor complexes at the plasma membrane is phylogenetically plausible. There is no direct IRAK3 localisation evidence at the plasma membrane and its observed location is cytoplasm/nucleus, so this is kept only as non-core. Supporting Evidence: PMID:38268724 Surface 1, with central residue Trp74, binds to MyD88/IRAK-4. file:human/IRAK3/IRAK3-uniprot.txt Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily. |
| GO:0006468 protein phosphorylation | IDA PMID:10383454 IRAK-M is a novel member of the Pelle/interleukin-1 receptor... | REMOVE | Summary: IRAK3 does not catalyse protein phosphorylation; only negligible autophosphorylation was reported and the catalytic residues are absent. Reason: Protein kinase activity requires a catalytic aspartate that IRAK3 lacks (HRD replaced by CGS), and this substitution is conserved across 134 vertebrate IRAK3 orthologues. The discovery paper reports only negligible autophosphorylation, the structure paper describes IRAK3 as a pseudokinase lacking catalytic activity, and no physiological phosphorylation substrate has been identified. UniProt flags the active-site substitution in a curated CAUTION. The kinase-domain fold is used for protein interaction (head-to-head homodimer, transient complex with phosphorylated IRAK4), not phosphotransfer. Transfer of protein kinase activity from the catalytically active IRAK1/IRAK4 subfamilies is not justified for the IRAK3 subfamily (PTHR24419:SF7). Removed for all rows of this claim. The same reasoning applies to protein phosphorylation as a process: IRAK3 regulates phosphorylation of other IRAKs indirectly (by retaining IRAK1/IRAK4 on MyD88), which is captured by the regulatory process terms, but it does not perform phosphorylation. Supporting Evidence: PMID:10383454 Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. PMID:33238146 In contrast to the active kinases IRAK1 and IRAK4, IRAK2 and IRAK3 are pseudokinases lacking catalytic activity and their functions are poorly understood. PMID:33238146 The canonical catalytic βHRDβ-motif is missing entirely in IRAK3 and replaced with βCGS,β whereas the Mg2+-coordinating βDFGβ-motif is slightly altered to βDFA.β |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: Signal transduction from the InterPro death-domain mapping is true but very general. Reason: IRAK3 participates in MyD88-dependent TLR and IL-1 receptor signaling, both already annotated. The death-domain InterPro mapping to signal transduction is correct but uninformative; the specific supported process is MyD88-dependent toll-like receptor signaling pathway. Proposed replacements: MyD88-dependent toll-like receptor signaling pathway Supporting Evidence: PMID:23376919 IRAK-M was also able to interact with MyD88-IRAK-4 to form IRAK-M Myddosome to mediate TLR7-induced MEKK3-dependent second wave NFΞΊB activation PMID:38268724 Surface 1, with central residue Trp74, binds to MyD88/IRAK-4. |
| GO:0008063 Toll signaling pathway | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: GO:0008063 is defined as signaling initiated through the Drosophila receptor Toll; the vertebrate counterpart is TLR signaling. Reason: The IBA comes from node PTN000701353, seeded only by Drosophila Pelle and Tube, which act in the Toll pathway. GO:0008063 is defined by ligand binding to the receptor Toll; vertebrates use Toll-like receptors and IL-1 receptors, which the gene already carries (MyD88-dependent TLR signaling, IL-1-mediated signaling). The node placement captures a real ancestral role in Toll/IL-1R-family signaling, but the specific Toll term over-states it for a vertebrate-restricted IRAK3 subfamily member, so it is marked as over-annotated rather than removed. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: LINEAGE OR TAXON MISMATCH Sources checked: PANTHER:PTN000701353 Β· PTN000701353 SUPPORTS SOURCE BUT NOT TARGET Node seeded by Drosophila Pelle and Tube in the Toll pathway. IRAK3 is inside the IRAK/Pelle clade, so an ancestral role in Toll/IL-1R-family signaling is sound, but the Drosophila-receptor-specific Toll term does not describe vertebrate TLR/IL-1R signaling. Supporting Evidence: file:human/IRAK3/IRAK3-uniprot.txt Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily. PMID:12150927 We show here that IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling. |
| GO:0009615 response to virus | IC PMID:12150927 IRAK-M is a negative regulator of Toll-like receptor signali... | MARK AS OVER ANNOTATED | Summary: Response to virus is inferred (IC) from a dsRNA response annotation, and by ARBA; no viral infection data exist for IRAK3 in the cited work. Reason: The cited mouse study used bacterial challenge and TLR ligands, not virus infection. Inferring response to virus from a response to a synthetic dsRNA ligand overextends a regulatory role in TLR signaling; IRAK3 is better described by negative regulation of TLR signaling. Marked over-annotated. Supporting Evidence: PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. PMID:12150927 We show here that IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling. |
| GO:0009615 response to virus | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Response to virus is inferred (IC) from a dsRNA response annotation, and by ARBA; no viral infection data exist for IRAK3 in the cited work. Reason: The cited mouse study used bacterial challenge and TLR ligands, not virus infection. Inferring response to virus from a response to a synthetic dsRNA ligand overextends a regulatory role in TLR signaling; IRAK3 is better described by negative regulation of TLR signaling. Marked over-annotated. Supporting Evidence: PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. PMID:12150927 We show here that IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling. |
| GO:0010933 positive regulation of macrophage tolerance induction | IEA GO_REF:0000107 | ACCEPT | Summary: IRAK3 is required for endotoxin tolerance in macrophages. Reason: Endotoxin tolerance was significantly reduced in IRAK-M-deficient cells (mouse), and IRAK3 is induced by TLR stimulation as a feedback inhibitor. Human and mouse IRAK3 are orthologues in the same PANTHER subfamily (PTHR24419:SF7), so transfer of this regulatory role is justified. This is a core physiological output of its negative-feedback function. Supporting Evidence: PMID:12150927 Endotoxin tolerance, a protection mechanism against endotoxin shock, was significantly reduced in IRAK-M(-/-) cells. PMID:12150927 We show here that IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling. |
| GO:0010933 positive regulation of macrophage tolerance induction | ISS PMID:12150927 IRAK-M is a negative regulator of Toll-like receptor signali... | ACCEPT | Summary: IRAK3 is required for endotoxin tolerance in macrophages. Reason: Endotoxin tolerance was significantly reduced in IRAK-M-deficient cells (mouse), and IRAK3 is induced by TLR stimulation as a feedback inhibitor. Human and mouse IRAK3 are orthologues in the same PANTHER subfamily (PTHR24419:SF7), so transfer of this regulatory role is justified. This is a core physiological output of its negative-feedback function. Supporting Evidence: PMID:12150927 Endotoxin tolerance, a protection mechanism against endotoxin shock, was significantly reduced in IRAK-M(-/-) cells. PMID:12150927 We show here that IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling. |
| GO:0010936 negative regulation of macrophage cytokine production | IEA GO_REF:0000107 | ACCEPT | Summary: IRAK3 restrains TLR-induced cytokine production by macrophages. Reason: IRAK-M-deficient macrophages show increased cytokine production upon TLR/IL-1 stimulation; in human THP-1 macrophages and monocytes IRAK3 knockdown augments TNF, IL-6 and IL-12 p40. Core regulatory role, conserved within PTHR24419:SF7. Supporting Evidence: PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. PMID:18156187 Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages |
| GO:0010936 negative regulation of macrophage cytokine production | ISS PMID:12150927 IRAK-M is a negative regulator of Toll-like receptor signali... | ACCEPT | Summary: IRAK3 restrains TLR-induced cytokine production by macrophages. Reason: IRAK-M-deficient macrophages show increased cytokine production upon TLR/IL-1 stimulation; in human THP-1 macrophages and monocytes IRAK3 knockdown augments TNF, IL-6 and IL-12 p40. Core regulatory role, conserved within PTHR24419:SF7. Supporting Evidence: PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. PMID:18156187 Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages |
| GO:0019221 cytokine-mediated signaling pathway | IEA GO_REF:0000107 | MODIFY | Summary: Cytokine-mediated signaling transferred from mouse; IRAK3 acts in IL-1 and IL-33 receptor (IL-1R family) signaling. Reason: IRAK3 is part of the IL-1R/TLR MyD88-IRAK4 machinery and is required for IL-33 signaling in dendritic cells. The general cytokine-mediated signaling term is correct but should be refined to the specific supported pathways: interleukin-1-mediated signaling pathway (already annotated) and interleukin-33-mediated signaling pathway. Proposed replacements: interleukin-1-mediated signaling pathway interleukin-33-mediated signaling pathway Supporting Evidence: PMID:10383454 Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. PMID:29686383 Here we show that interleukin receptor associated kinase M (IRAK-M) is a PIN1 target critical for IL-33 signaling in allergic asthma. |
| GO:0019221 cytokine-mediated signaling pathway | ISS GO_REF:0000024 | MODIFY | Summary: Cytokine-mediated signaling transferred from mouse; IRAK3 acts in IL-1 and IL-33 receptor (IL-1R family) signaling. Reason: IRAK3 is part of the IL-1R/TLR MyD88-IRAK4 machinery and is required for IL-33 signaling in dendritic cells. The general cytokine-mediated signaling term is correct but should be refined to the specific supported pathways: interleukin-1-mediated signaling pathway (already annotated) and interleukin-33-mediated signaling pathway. Proposed replacements: interleukin-1-mediated signaling pathway interleukin-33-mediated signaling pathway Supporting Evidence: PMID:10383454 Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. PMID:29686383 Here we show that interleukin receptor associated kinase M (IRAK-M) is a PIN1 target critical for IL-33 signaling in allergic asthma. |
| GO:0019901 protein kinase binding | IPI PMID:33238146 Dimeric Structure of the Pseudokinase IRAK3 Suggests an Allo... | ACCEPT | Summary: The IRAK3 pseudokinase domain forms a transient complex with the phosphorylated IRAK4 kinase domain; IRAK3 also binds the MyD88-IRAK4 complex through its death domain. Reason: Native PAGE co-migration showed a transient complex between the IRAK3 pseudokinase domain and phosphorylated IRAK4 kinase domain, and the structure identified a conserved C-lobe surface resembling the IRAK4 dimer interface. Death-domain mutagenesis shows Trp74 binds MyD88/IRAK-4. Binding to the kinase IRAK4 is central to how IRAK3 retains IRAK4/IRAK1 on MyD88 and redirects signaling, making this the best available core MF term. Supporting Evidence: PMID:33238146 This indicates the formation of a transient complex between the pseudokinase domain of IRAK3 and the phosphorylated kinase domain of IRAK4. PMID:38268724 Surface 1, with central residue Trp74, binds to MyD88/IRAK-4. |
| GO:0031663 lipopolysaccharide-mediated signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IRAK3 is an induced component of TLR4/LPS signaling that limits its output. Reason: IRAK3 is induced by LPS and acts at the MyD88-IRAK complex in LPS signaling; IRAK3 knockdown in THP-1 macrophages augments LPS-induced cytokines, and the original work showed IRAK family members are required for LPS signal transduction. The IBA node PTN000701353 (IRAK/Pelle clade including IRAK3, with IRAK3 itself among the donors) places this role ancestrally. Accepted as participation in the pathway as its feedback component. Supporting Evidence: PMID:18156187 Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages PMID:10383454 In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. |
| GO:0031663 lipopolysaccharide-mediated signaling pathway | IMP PMID:18156187 Early and preferential induction of IL-1 receptor-associated... | ACCEPT | Summary: IRAK3 is an induced component of TLR4/LPS signaling that limits its output. Reason: IRAK3 is induced by LPS and acts at the MyD88-IRAK complex in LPS signaling; IRAK3 knockdown in THP-1 macrophages augments LPS-induced cytokines, and the original work showed IRAK family members are required for LPS signal transduction. The IBA node PTN000701353 (IRAK/Pelle clade including IRAK3, with IRAK3 itself among the donors) places this role ancestrally. Accepted as participation in the pathway as its feedback component. Supporting Evidence: PMID:18156187 Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages PMID:10383454 In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. |
| GO:0032494 response to peptidoglycan | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Altered responses to peptidoglycan/TLR2 ligands in IRAK-M-deficient cells. Reason: Response-to-stimulus terms are derived from altered cytokine output of IRAK-M-deficient cells. They are true, because IRAK3 is induced by and modulates responses to bacterial ligands, but they are downstream readouts of its regulatory role in TLR signaling; the more precise regulatory terms carry the core function. Supporting Evidence: PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. |
| GO:0032494 response to peptidoglycan | ISS PMID:12150927 IRAK-M is a negative regulator of Toll-like receptor signali... | KEEP AS NON CORE | Summary: Altered responses to peptidoglycan/TLR2 ligands in IRAK-M-deficient cells. Reason: Response-to-stimulus terms are derived from altered cytokine output of IRAK-M-deficient cells. They are true, because IRAK3 is induced by and modulates responses to bacterial ligands, but they are downstream readouts of its regulatory role in TLR signaling; the more precise regulatory terms carry the core function. Supporting Evidence: PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. |
| GO:0032496 response to lipopolysaccharide | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IRAK3 is induced by and modulates responses to LPS. Reason: Response-to-stimulus terms are derived from altered cytokine output of IRAK-M-deficient cells. They are true, because IRAK3 is induced by and modulates responses to bacterial ligands, but they are downstream readouts of its regulatory role in TLR signaling; the more precise regulatory terms carry the core function. Supporting Evidence: PMID:12150927 We show here that IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling. PMID:18156187 Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages |
| GO:0032496 response to lipopolysaccharide | ISS PMID:12150927 IRAK-M is a negative regulator of Toll-like receptor signali... | KEEP AS NON CORE | Summary: IRAK3 is induced by and modulates responses to LPS. Reason: Response-to-stimulus terms are derived from altered cytokine output of IRAK-M-deficient cells. They are true, because IRAK3 is induced by and modulates responses to bacterial ligands, but they are downstream readouts of its regulatory role in TLR signaling; the more precise regulatory terms carry the core function. Supporting Evidence: PMID:12150927 We show here that IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling. PMID:18156187 Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages |
| GO:0032695 negative regulation of interleukin-12 production | IEA GO_REF:0000120 | ACCEPT | Summary: IRAK3 knockdown increases LPS-induced IL-12 p40 in human macrophages; knockout increases cytokines in mouse. Reason: Direct loss-of-function evidence in human THP-1-derived macrophages and mouse knockouts; IL-12 is among the cytokines restrained by IRAK3 negative feedback. Supporting Evidence: PMID:18156187 Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. |
| GO:0032695 negative regulation of interleukin-12 production | IMP PMID:18156187 Early and preferential induction of IL-1 receptor-associated... | ACCEPT | Summary: IRAK3 knockdown increases LPS-induced IL-12 p40 in human macrophages; knockout increases cytokines in mouse. Reason: Direct loss-of-function evidence in human THP-1-derived macrophages and mouse knockouts; IL-12 is among the cytokines restrained by IRAK3 negative feedback. Supporting Evidence: PMID:18156187 Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. |
| GO:0032695 negative regulation of interleukin-12 production | ISS PMID:12150927 IRAK-M is a negative regulator of Toll-like receptor signali... | ACCEPT | Summary: IRAK3 knockdown increases LPS-induced IL-12 p40 in human macrophages; knockout increases cytokines in mouse. Reason: Direct loss-of-function evidence in human THP-1-derived macrophages and mouse knockouts; IL-12 is among the cytokines restrained by IRAK3 negative feedback. Supporting Evidence: PMID:18156187 Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. |
| GO:0032715 negative regulation of interleukin-6 production | IEA GO_REF:0000120 | ACCEPT | Summary: IRAK3 knockdown increases LPS-induced IL-6 in human macrophages; knockout increases cytokines in mouse. Reason: Direct loss-of-function evidence in human THP-1-derived macrophages and mouse knockouts; also, the Arg97 death-domain surface is engaged in IL-6 down-regulation. Supporting Evidence: PMID:18156187 Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. |
| GO:0032715 negative regulation of interleukin-6 production | IMP PMID:18156187 Early and preferential induction of IL-1 receptor-associated... | ACCEPT | Summary: IRAK3 knockdown increases LPS-induced IL-6 in human macrophages; knockout increases cytokines in mouse. Reason: Direct loss-of-function evidence in human THP-1-derived macrophages and mouse knockouts; also, the Arg97 death-domain surface is engaged in IL-6 down-regulation. Supporting Evidence: PMID:18156187 Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. |
| GO:0032715 negative regulation of interleukin-6 production | ISS PMID:12150927 IRAK-M is a negative regulator of Toll-like receptor signali... | ACCEPT | Summary: IRAK3 knockdown increases LPS-induced IL-6 in human macrophages; knockout increases cytokines in mouse. Reason: Direct loss-of-function evidence in human THP-1-derived macrophages and mouse knockouts; also, the Arg97 death-domain surface is engaged in IL-6 down-regulation. Supporting Evidence: PMID:18156187 Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. |
| GO:0032720 negative regulation of tumor necrosis factor production | IEA GO_REF:0000120 | ACCEPT | Summary: IRAK3 knockdown restores TNF production in tumor-deactivated human monocytes and LPS-stimulated macrophages. Reason: siRNA knockdown of IRAK3 reinstated TNF mRNA and protein in human monocytes re-exposed to tumor cells, and augmented TNF in LPS-stimulated THP-1 macrophages. Supporting Evidence: PMID:15728517 down-regulation of IRAK-M expression by small interfering RNAs specific for IRAK-M reinstates both TNF-alpha mRNA expression and protein production in human monocytes re-exposed to a tumor cell line PMID:18156187 Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages |
| GO:0032720 negative regulation of tumor necrosis factor production | IMP PMID:15728517 Tumor cells deactivate human monocytes by up-regulating IL-1... | ACCEPT | Summary: IRAK3 knockdown restores TNF production in tumor-deactivated human monocytes and LPS-stimulated macrophages. Reason: siRNA knockdown of IRAK3 reinstated TNF mRNA and protein in human monocytes re-exposed to tumor cells, and augmented TNF in LPS-stimulated THP-1 macrophages. Supporting Evidence: PMID:15728517 down-regulation of IRAK-M expression by small interfering RNAs specific for IRAK-M reinstates both TNF-alpha mRNA expression and protein production in human monocytes re-exposed to a tumor cell line PMID:18156187 Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages |
| GO:0034122 negative regulation of toll-like receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: IRAK3 is a TLR-induced negative feedback regulator of TLR signaling. Reason: Core function: IRAK3 prevents dissociation of IRAK1/IRAK4 from MyD88 and IRAK1-TRAF6 complex formation, and its loss increases TLR responses and reduces endotoxin tolerance. Human and mouse IRAK3 share PANTHER subfamily PTHR24419:SF7; human knockdown data agree. Supporting Evidence: PMID:12150927 We show here that IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling. PMID:12150927 IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. PMID:25481771 IRAK-M inhibited TLR2/4-mediated cytokine production in macrophages in a manner that is largely dependent on W74. |
| GO:0034122 negative regulation of toll-like receptor signaling pathway | ISS PMID:12150927 IRAK-M is a negative regulator of Toll-like receptor signali... | ACCEPT | Summary: IRAK3 is a TLR-induced negative feedback regulator of TLR signaling. Reason: Core function: IRAK3 prevents dissociation of IRAK1/IRAK4 from MyD88 and IRAK1-TRAF6 complex formation, and its loss increases TLR responses and reduces endotoxin tolerance. Human and mouse IRAK3 share PANTHER subfamily PTHR24419:SF7; human knockdown data agree. Supporting Evidence: PMID:12150927 We show here that IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling. PMID:12150927 IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. PMID:25481771 IRAK-M inhibited TLR2/4-mediated cytokine production in macrophages in a manner that is largely dependent on W74. |
| GO:0035556 intracellular signal transduction | IBA GO_REF:0000033 | MODIFY | Summary: Intracellular signal transduction from a deep IRAK/Pelle kinase IBA node is true but general for IRAK3. Reason: IRAK3 functions in MyD88-dependent TLR and IL-1R signaling, which are more specific supported processes already annotated. The general term is correct and phylogenetically sound but can be refined. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000784925 Β· PTN000784925 SUPPORTS TRANSFER Deep kinase-superfamily node; intracellular signal transduction holds for IRAK3, but the specific MyD88-dependent TLR pathway is supported and already annotated. Proposed replacements: MyD88-dependent toll-like receptor signaling pathway Supporting Evidence: PMID:23376919 IRAK-M was also able to interact with MyD88-IRAK-4 to form IRAK-M Myddosome to mediate TLR7-induced MEKK3-dependent second wave NFΞΊB activation PMID:38268724 Surface 1, with central residue Trp74, binds to MyD88/IRAK-4. |
| GO:0042177 negative regulation of protein catabolic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IRAK3 stabilises the phosphatase MKP-1 after TLR2 stimulation. Reason: In IRAK-M-deficient BMDM and THP-1 knockdown cells MKP-1 protein decreased rapidly after Pam3CSK4, consistent with IRAK3 limiting MKP-1 degradation. The mechanism is not defined and the evidence is from one study, so the term is kept as non-core. Supporting Evidence: PMID:17379480 Our findings indicate that IRAK-M selectively attenuates p38 activation and inhibits innate immunity through stabilizing MKP-1. |
| GO:0042177 negative regulation of protein catabolic process | IMP PMID:17379480 Differential regulation and role of interleukin-1 receptor a... | KEEP AS NON CORE | Summary: IRAK3 stabilises the phosphatase MKP-1 after TLR2 stimulation. Reason: In IRAK-M-deficient BMDM and THP-1 knockdown cells MKP-1 protein decreased rapidly after Pam3CSK4, consistent with IRAK3 limiting MKP-1 degradation. The mechanism is not defined and the evidence is from one study, so the term is kept as non-core. Supporting Evidence: PMID:17379480 Our findings indicate that IRAK-M selectively attenuates p38 activation and inhibits innate immunity through stabilizing MKP-1. |
| GO:0042803 protein homodimerization activity | IDA PMID:33238146 Dimeric Structure of the Pseudokinase IRAK3 Suggests an Allo... | ACCEPT | Summary: IRAK3 forms a head-to-head homodimer of its pseudokinase domain, also disulfide-linked. Reason: The crystal structure and solution mutagenesis (L210E dimer-disrupting, E214L stabilising) establish a distinct homodimer; death-domain Lys60 surface supports homotetramerisation under MyD88/IRAK-4. Homo-oligomerisation is an intrinsic, conserved property of IRAK3 relevant to its regulatory mechanism. Supporting Evidence: PMID:33238146 IRAK3 dimerizes in a unique way through a head-to-head arrangement not observed in any other kinases. file:human/IRAK3/IRAK3-uniprot.txt Homodimer; disulfide-linked |
| GO:0042803 protein homodimerization activity | IPI PMID:10383454 IRAK-M is a novel member of the Pelle/interleukin-1 receptor... | ACCEPT | Summary: IRAK3 forms a head-to-head homodimer of its pseudokinase domain, also disulfide-linked. Reason: The crystal structure and solution mutagenesis (L210E dimer-disrupting, E214L stabilising) establish a distinct homodimer; death-domain Lys60 surface supports homotetramerisation under MyD88/IRAK-4. Homo-oligomerisation is an intrinsic, conserved property of IRAK3 relevant to its regulatory mechanism. Supporting Evidence: PMID:33238146 IRAK3 dimerizes in a unique way through a head-to-head arrangement not observed in any other kinases. file:human/IRAK3/IRAK3-uniprot.txt Homodimer; disulfide-linked |
| GO:0043122 regulation of canonical NF-kappaB signal transduction | IEA GO_REF:0000117 | MODIFY | Summary: IRAK3 regulates canonical NF-kB signaling in both directions depending on context. Reason: IRAK3 inhibits TAK1-dependent NF-kB activation by blocking IRAK1-TRAF6 coupling, but the IRAK-M myddosome drives MEKK3-dependent second-wave NF-kB that induces inhibitory genes. Both specific descendants are supported, so the general regulation term is refined to list both. Proposed replacements: negative regulation of canonical NF-kappaB signal transduction positive regulation of canonical NF-kappaB signal transduction Supporting Evidence: PMID:12150927 IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. PMID:23376919 IRAK-M was also able to interact with MyD88-IRAK-4 to form IRAK-M Myddosome to mediate TLR7-induced MEKK3-dependent second wave NFΞΊB activation |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IRAK3 can drive MEKK3-dependent second-wave NF-kB activation through an IRAK-M myddosome. Reason: The IBA (node PTN008405164, IRAK clade) is supported for IRAK3 specifically: IRAK-M forms a MyD88-IRAK4-IRAK-M myddosome that activates MEKK3-dependent NF-kB, and overexpressed IRAK3 activates NF-kB in 293T cells dependent on death-domain Trp74 and Arg97. The net output of this branch is inhibitory gene expression, so positive NF-kB regulation is a mechanistic, context-specific role kept as non-core. Supporting Evidence: PMID:23376919 IRAK-M was also able to interact with MyD88-IRAK-4 to form IRAK-M Myddosome to mediate TLR7-induced MEKK3-dependent second wave NFΞΊB activation PMID:23376919 IRAK-M mediates TLR7-induced MEKK3-dependent second wave NFΞΊB activation to produce inhibitory molecules as a negative feedback for the pathway PMID:38268724 IRAK-M has also been reported to activate NF-ΞΊB through the MyD88/IRAK-4/IRAK-M myddosome in a MEKK-3 dependent manner. |
| GO:0043124 negative regulation of canonical NF-kappaB signal transduction | IMP PMID:10383454 IRAK-M is a novel member of the Pelle/interleukin-1 receptor... | ACCEPT | Summary: IRAK3 inhibits canonical TAK1-dependent NF-kB activation downstream of TLR/IL-1R. Reason: IRAK3 prevents IRAK1-TRAF6 complex formation and IRAK release from MyD88, and its loss increases TLR/IL-1-induced cytokines. Deferring to the curator who read the full text of PMID:10383454; the claim is consistent with the later genetic evidence. Supporting Evidence: PMID:12150927 IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. |
| GO:0043242 negative regulation of protein-containing complex disassembly | IMP PMID:12150927 IRAK-M is a negative regulator of Toll-like receptor signali... | ACCEPT | Summary: IRAK3 prevents dissociation of IRAK1 and IRAK4 from MyD88. Reason: This is the defining mechanistic finding for IRAK3: it prevents dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes, and in human THP-1 macrophages IRAK3 induction suppresses IRAK-1 dissociation/degradation. Supporting Evidence: PMID:12150927 IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. PMID:18156187 Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages |
| GO:0043244 regulation of protein-containing complex disassembly | IEA GO_REF:0000120 | MODIFY | Summary: IRAK3 negatively regulates disassembly of MyD88-IRAK complexes; the general regulation term should be the specific negative term. Reason: The supported direction is negative (IRAK-M prevents dissociation of IRAK1/IRAK4 from MyD88), already annotated by IMP as GO:0043242. Proposed replacements: negative regulation of protein-containing complex disassembly Supporting Evidence: PMID:12150927 IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. |
| GO:0043244 regulation of protein-containing complex disassembly | ISS GO_REF:0000024 | MODIFY | Summary: IRAK3 negatively regulates disassembly of MyD88-IRAK complexes; the general regulation term should be the specific negative term. Reason: The supported direction is negative (IRAK-M prevents dissociation of IRAK1/IRAK4 from MyD88), already annotated by IMP as GO:0043242. Proposed replacements: negative regulation of protein-containing complex disassembly Supporting Evidence: PMID:12150927 IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. |
| GO:0043330 response to exogenous dsRNA | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Altered responses to dsRNA ligand in IRAK-M-deficient cells (mouse), transferred to human. Reason: Response-to-stimulus terms are derived from altered cytokine output of IRAK-M-deficient cells. They are true, because IRAK3 is induced by and modulates responses to bacterial ligands, but they are downstream readouts of its regulatory role in TLR signaling; the more precise regulatory terms carry the core function. The cached abstract does not specify the dsRNA experiment; the curator of the mouse source presumably read the full text, so the row is kept, but as a non-core downstream readout. Supporting Evidence: PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. |
| GO:0043330 response to exogenous dsRNA | ISS PMID:12150927 IRAK-M is a negative regulator of Toll-like receptor signali... | KEEP AS NON CORE | Summary: Altered responses to dsRNA ligand in IRAK-M-deficient cells (mouse), transferred to human. Reason: Response-to-stimulus terms are derived from altered cytokine output of IRAK-M-deficient cells. They are true, because IRAK3 is induced by and modulates responses to bacterial ligands, but they are downstream readouts of its regulatory role in TLR signaling; the more precise regulatory terms carry the core function. The cached abstract does not specify the dsRNA experiment; the curator of the mouse source presumably read the full text, so the row is kept, but as a non-core downstream readout. Supporting Evidence: PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. |
| GO:0043409 negative regulation of MAPK cascade | IEA GO_REF:0000120 | MODIFY | Summary: IRAK3 selectively attenuates TLR2-induced p38 activation, not ERK or JNK. Reason: The evidence supports a selective effect on p38 activation (via MKP-1 stabilisation), so the general MAPK cascade term should be refined to negative regulation of p38MAPK cascade (GO:1903753). Proposed replacements: negative regulation of p38MAPK cascade Supporting Evidence: PMID:17379480 IRAK-M selectively attenuates bacterial lipopeptide Pam(3)CSK(4)-induced p38 activation, but not ERK or JNK. PMID:17379480 Our findings indicate that IRAK-M selectively attenuates p38 activation and inhibits innate immunity through stabilizing MKP-1. |
| GO:0043409 negative regulation of MAPK cascade | IMP PMID:17379480 Differential regulation and role of interleukin-1 receptor a... | MODIFY | Summary: IRAK3 selectively attenuates TLR2-induced p38 activation, not ERK or JNK. Reason: The evidence supports a selective effect on p38 activation (via MKP-1 stabilisation), so the general MAPK cascade term should be refined to negative regulation of p38MAPK cascade (GO:1903753). Proposed replacements: negative regulation of p38MAPK cascade Supporting Evidence: PMID:17379480 IRAK-M selectively attenuates bacterial lipopeptide Pam(3)CSK(4)-induced p38 activation, but not ERK or JNK. PMID:17379480 Our findings indicate that IRAK-M selectively attenuates p38 activation and inhibits innate immunity through stabilizing MKP-1. |
| GO:0045088 regulation of innate immune response | IEA GO_REF:0000117 | MODIFY | Summary: ARBA regulation of innate immune response; the supported direction is negative. Reason: IRAK3 restrains innate immune responses (increased inflammatory responses in knockouts); negative regulation of innate immune response is already annotated and is the specific descendant to use. Proposed replacements: negative regulation of innate immune response Supporting Evidence: PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. |
| GO:0045824 negative regulation of innate immune response | IEA GO_REF:0000107 | ACCEPT | Summary: IRAK3 is a negative regulator of innate immune responses. Reason: IRAK-M-deficient mice show increased inflammatory responses to bacterial infection and reduced endotoxin tolerance; conserved in PTHR24419:SF7 and consistent with human knockdown data. Supporting Evidence: PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. PMID:12150927 Endotoxin tolerance, a protection mechanism against endotoxin shock, was significantly reduced in IRAK-M(-/-) cells. |
| GO:0045824 negative regulation of innate immune response | ISS PMID:12150927 IRAK-M is a negative regulator of Toll-like receptor signali... | ACCEPT | Summary: IRAK3 is a negative regulator of innate immune responses. Reason: IRAK-M-deficient mice show increased inflammatory responses to bacterial infection and reduced endotoxin tolerance; conserved in PTHR24419:SF7 and consistent with human knockdown data. Supporting Evidence: PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. PMID:12150927 Endotoxin tolerance, a protection mechanism against endotoxin shock, was significantly reduced in IRAK-M(-/-) cells. |
| GO:0046982 protein heterodimerization activity | IPI PMID:10383454 IRAK-M is a novel member of the Pelle/interleukin-1 receptor... | KEEP AS NON CORE | Summary: IRAK3 associates with other IRAK family members (IRAK1, IRAK2) via death-domain surfaces. Reason: Co-immunoprecipitation of IRAK3 with IRAK1 and IRAK2 is supported by later mutagenesis showing Arg97 is pivotal for IRAK-M interaction with IRAK-1 and predicted IRAK-2 death-domain contact points. The cached 1999 abstract does not describe the experiment; deferring to the curator on the heterodimerization assignment. These hetero-associations are part of myddosome assembly but are secondary to the IRAK4/MyD88 interaction, so kept as non-core. Supporting Evidence: PMID:38268724 Arg97 was also found to be pivotal for IRAK-M's interaction with IRAK-1, and important for IRAK-M's interaction with TRAF6. |
| GO:0046982 protein heterodimerization activity | IPI PMID:10383454 IRAK-M is a novel member of the Pelle/interleukin-1 receptor... | KEEP AS NON CORE | Summary: IRAK3 associates with other IRAK family members (IRAK1, IRAK2) via death-domain surfaces. Reason: Co-immunoprecipitation of IRAK3 with IRAK1 and IRAK2 is supported by later mutagenesis showing Arg97 is pivotal for IRAK-M interaction with IRAK-1 and predicted IRAK-2 death-domain contact points. The cached 1999 abstract does not describe the experiment; deferring to the curator on the heterodimerization assignment. These hetero-associations are part of myddosome assembly but are secondary to the IRAK4/MyD88 interaction, so kept as non-core. Supporting Evidence: PMID:38268724 Arg97 was also found to be pivotal for IRAK-M's interaction with IRAK-1, and important for IRAK-M's interaction with TRAF6. |
| GO:0070498 interleukin-1-mediated signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IRAK3 is a component of IL-1 receptor signaling. Reason: IRAK3 reconstitutes the IL-1 response in IRAK-deficient 293 cells and acts on the MyD88-IRAK4 complex shared by IL-1R and TLRs; the IBA node PTN002815516 includes IRAK3 itself as an experimental donor. Supporting Evidence: PMID:10383454 Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. |
| GO:0070498 interleukin-1-mediated signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: IRAK3 is a component of IL-1 receptor signaling. Reason: IRAK3 reconstitutes the IL-1 response in IRAK-deficient 293 cells and acts on the MyD88-IRAK4 complex shared by IL-1R and TLRs; the IBA node PTN002815516 includes IRAK3 itself as an experimental donor. Supporting Evidence: PMID:10383454 Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. |
| GO:0070498 interleukin-1-mediated signaling pathway | IMP PMID:10383454 IRAK-M is a novel member of the Pelle/interleukin-1 receptor... | ACCEPT | Summary: IRAK3 is a component of IL-1 receptor signaling. Reason: IRAK3 reconstitutes the IL-1 response in IRAK-deficient 293 cells and acts on the MyD88-IRAK4 complex shared by IL-1R and TLRs; the IBA node PTN002815516 includes IRAK3 itself as an experimental donor. Supporting Evidence: PMID:10383454 Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. PMID:12150927 IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. |
| GO:0070555 response to interleukin-1 | IMP PMID:10383454 IRAK-M is a novel member of the Pelle/interleukin-1 receptor... | KEEP AS NON CORE | Summary: Response to IL-1 is implied by participation in IL-1 signaling. Reason: True, but the more informative IL-1-mediated signaling pathway term is already accepted; response to interleukin-1 is kept as non-core. Supporting Evidence: PMID:10383454 Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. |
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Download this section (compressed HTML)Q: Does IRAK3 have physiologically relevant guanylate cyclase activity in its pseudokinase domain, and does cGMP production contribute to its inhibition of NF-kB?
Q: Is the proposed IRAK3-IRAK4 C-lobe hetero-oligomer the mechanism by which IRAK3 retains IRAK4 on MyD88 in cells?
Q: What does nuclear IRAK3 do after IL-33/PIN1 signaling, and is nuclear translocation conserved in human dendritic cells?
Experiment: Reconstitute IRAK3-deficient human macrophages with dimer-disrupting (L210E) or IRAK4-interface (C-lobe) mutants and measure IRAK1 release from MyD88 and cytokine output.
Experiment: Quantify cGMP production by purified full-length IRAK3 versus guanylate-cyclase-centre mutants under physiological nucleotide concentrations.
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