{"gene":"IRAK2","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1997,"finding":"IRAK-2 and MyD88 are proximal mediators of IL-1R signaling that both associate with the IL-1R signaling complex; dominant negative forms of either attenuate IL-1R-mediated NF-κB activation.","method":"Co-immunoprecipitation, dominant-negative overexpression, NF-κB reporter assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP of complex formation plus dominant-negative functional validation, foundational paper replicated extensively by subsequent work","pmids":["9374458"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of the MyD88-IRAK4-IRAK2 death domain (Myddosome) complex reveals a left-handed helical oligomer of 6 MyD88, 4 IRAK4, and 4 IRAK2 DDs; assembly is hierarchical (MyD88 recruits IRAK4, then IRAK4 recruits IRAK2/IRAK1); composite binding sites are required, confirmed by mutagenesis; proximity of kinase domains enables phosphorylation/activation.","method":"X-ray crystallography, site-directed mutagenesis, functional signaling assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validation, published in Nature, widely replicated","pmids":["20485341"],"is_preprint":false},{"year":2008,"finding":"IRAK2 is essential for sustaining late-phase (peaking ~8 h) TLR-induced NF-κB activation and cytokine gene expression downstream of IRAK4; its kinase activity is sustained whereas IRAK1 kinase activity and protein levels decline within 1 h. TLR-induced cytokine production is abolished only in cells lacking both IRAK1 and IRAK2.","method":"IRAK1/IRAK2 knockout mouse macrophages, kinase activity assays, cytokine production measurements, NF-κB reporter assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout in primary immune cells with multiple orthogonal phenotypic readouts, replicated in subsequent knock-in studies","pmids":["18438411"],"is_preprint":false},{"year":2007,"finding":"IRAK-2 is critical for TLR-mediated NF-κB activation across multiple TLRs (TLR2, 3, 4, 5, 7, 8, 9); IRAK-2 acts downstream of MyD88/Mal but upstream of TRIF; expression of IRAK-2 (but not IRAK-1) drives TRAF6 K63-linked ubiquitination, a critical step for NF-κB activation; loss-of-function IRAK-2 mutants that cannot activate NF-κB also fail to promote TRAF6 ubiquitination.","method":"siRNA knockdown in human cell lines and primary cells, overexpression assays, TRAF6 ubiquitination assay, NF-κB reporter assay, poxviral antagonist A52 interaction studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple TLRs tested, primary human cells, loss-of-function mutants linked mechanistically to TRAF6 ubiquitination, replicated in other labs","pmids":["17878161"],"is_preprint":false},{"year":2013,"finding":"The IRAK2-TRAF6 interaction (via IRAK2 E525) is required for the late phase (2–8 h) but not early phase (0–2 h) of IL-6 and TNF-α mRNA production and secretion in bone marrow-derived macrophages stimulated via MyD88-dependent TLRs; the IRAK2-TRAF6 interaction sustains IKKβ activity during prolonged MyD88 network activation; in plasmacytoid dendritic cells, IRAK2-TRAF6 interaction is needed for IFN-α (but not IFN-β) production.","method":"IRAK2[E525A] and IRAK1[D359A] knock-in mice, BMDM and pDC cytokine assays, IKKβ activity assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mice with precise mutation at TRAF6-binding site, multiple cell types and cytokine readouts, rigorous controls","pmids":["23918981"],"is_preprint":false},{"year":2020,"finding":"IL-1 induces IRAK2 Myddosome recruitment to mitochondrial outer membranes via TOM20 recognition, followed by TIMM50-guided translocation into mitochondrial inner membranes; mitochondrial IRAK2 suppresses oxidative phosphorylation and fatty acid oxidation by interacting with PHB1 and OPA1, thereby disrupting respiratory super-complex formation. Adipocyte-specific MyD88 or IRAK2 deficiency reduces high-fat diet-induced weight gain and improves insulin resistance.","method":"Mitochondrial fractionation, co-immunoprecipitation (IRAK2 with TOM20, TIMM50, PHB1, OPA1), adipocyte-specific conditional KO mice, IRAK2 kinase-inactive knockin mice, metabolic phenotyping, Seahorse assay","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (fractionation, Co-IP, conditional KO, kinase-dead knockin) in single rigorous study published in Nature immunology","pmids":["32778760"],"is_preprint":false},{"year":2017,"finding":"LPS/TLR4 engagement promotes nuclear localization of IRAK2; IRAK2 kinase activity is required for RanBP2-mediated IRAK2 sumoylation and subsequent nuclear translocation; nuclear IRAK2 phosphorylates SRSF1 to reduce its binding to target mRNAs, promoting ALYREF binding and Nxf1 loading for nuclear export of a specific subset of inflammatory mRNAs (enriched for SRSF1-binding motifs) in murine macrophages.","method":"Nuclear fractionation/localization assays, IRAK2 kinase mutant analysis, sumoylation assays, RNA-binding and nuclear export assays, mRNA array analysis, phosphorylation of SRSF1 in vitro","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (fractionation, sumoylation, SRSF1 phosphorylation, mRNA export assay) in a single study; novel mechanism","pmids":["28990926"],"is_preprint":false},{"year":2013,"finding":"IRAK2 contributes to ER stress-mediated unfolded protein response signaling specifically through the IRE1 pathway; knockdown of IRAK2 suppresses ER stress-induced CHOP expression and stress kinase activation; ER stress induces IRAK2 gene expression in an IRE1/XBP1-dependent manner, creating a positive amplification loop; Irak2 knockout mice show defects in ER stress-induced CHOP expression and IRE1 signaling.","method":"siRNA kinome screen, RNAi knockdown in mammalian and Drosophila cells, Irak2 knockout mice, ER stress induction assays, UPR pathway analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mice plus cell-based pathway analysis, but single lab and no reconstitution/structural validation","pmids":["23724040"],"is_preprint":false},{"year":2004,"finding":"The murine Irak2 gene encodes four alternatively spliced isoforms (Irak2a–d); Irak2a and Irak2b (containing intact death domain) potentiate NF-κB activation; Irak2c and Irak2d are inhibitory; LPS induces Irak2c expression via an NF-κB-responsive promoter, suggesting a negative feedback mechanism. No equivalent alternative splicing was found for human IRAK2.","method":"Molecular cloning, alternative splicing analysis, NF-κB reporter overexpression assays, LPS stimulation, promoter analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — molecular cloning with functional overexpression assays and promoter analysis, single lab","pmids":["15082713"],"is_preprint":false},{"year":2002,"finding":"Murine IRAK-2 shares 67% sequence identity with human IRAK-2, is ubiquitously expressed, and both murine and human forms practically lack autophosphorylation kinase activity; unlike human IRAK-2, murine IRAK-2 has no stimulatory effect on IL-1-induced NF-κB activation when overexpressed.","method":"Molecular cloning, sequence analysis, autophosphorylation kinase assay, NF-κB reporter overexpression assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vitro kinase assay and functional reporter assay; single lab but two orthogonal methods","pmids":["12220507"],"is_preprint":false},{"year":2009,"finding":"A deletion in the MOLF/Ei promoter of the inhibitory Irak2c isoform increases the ratio of pro- to anti-inflammatory IRAK-2 isoforms, leading to enhanced early NF-κB activity and p38 MAPK activation in TLR signaling; congenic mapping identified Irak2 as the causative gene at the Why1 locus.","method":"Genetic mapping (congenic mice), promoter deletion analysis, NF-κB and MAPK phosphorylation assays, LPS stimulation of primary macrophages","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by congenic mapping combined with biochemical signaling readouts, single lab","pmids":["19564352"],"is_preprint":false},{"year":2001,"finding":"Active Ras associates with IRAK, IRAK2, TRAF6, and TAK-1 in the IL-1 signaling complex; dominant-negative RasN17 blocks p38 MAPK activation downstream of TRAF6 but upstream of MKK3/MKK6; Ras likely aids assembly of the IRAK-TRAF6-TAK1 multiprotein complex required for IL-1-induced p38 MAPK activation.","method":"Co-immunoprecipitation of active RasVHa with signaling components, dominant-negative transfection epistasis, p38 MAPK activation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP plus dominant-negative epistasis, single lab, two orthogonal approaches","pmids":["11744690"],"is_preprint":false},{"year":2003,"finding":"IRAK2 and MyD88 (but not IRAK1) physically interact with Akt, as shown by co-immunoprecipitation and pull-down; the IRAK2-Akt association decreases upon IL-1 stimulation and is regulated by PTEN and PDK1; Akt kinase activity is required for IRAK2-dependent (but not IRAK1-dependent) NF-κB transactivation, acting at a step distinct from IκBα dissociation/p65 nuclear translocation.","method":"Co-immunoprecipitation, GST pull-down, NF-κB reporter assay with dominant-negative Akt, iNOS/IL-1β production assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal Co-IP and pull-down plus functional reporter validation, single lab","pmids":["12906710"],"is_preprint":false},{"year":2011,"finding":"IRAK-2 mediates pathological Th17 cell development in a CD4 T cell-intrinsic manner by enhancing IL-1β-induced activation of transcription factors RORγt and BATF, as established by adoptive transfer of CD4 T cells from Why1 congenic (Irak2-variant) mice.","method":"Adoptive transfer of CD4 T cells, Schistosoma mansoni infection model, RORγt/BATF transcription factor activation assays, congenic mouse genetics","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — adoptive transfer cleanly assigns cell-intrinsic function, supported by transcription factor readouts, single lab","pmids":["21998578"],"is_preprint":false},{"year":2015,"finding":"The IRAK2 coding variant L392V (rs3844283) shows intact binding to TRAF6 but impaired TRAF6 ubiquitination, resulting in reduced TLR-mediated cytokine and IFN-α induction in primary plasmacytoid dendritic cells; this hypofunctional variant is associated with reduced spontaneous HCV clearance.","method":"Co-immunoprecipitation (IRAK2-TRAF6 binding), ubiquitination assay, primary pDC cytokine/IFN assays, epidemiological cohort analysis","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and ubiquitination assay for mechanism, primary human cells, single lab","pmids":["26250868"],"is_preprint":false},{"year":2014,"finding":"The IRAK2 coding variant R214G (rs35060588) is hypofunctional for NF-κB signaling and TLR-mediated cytokine induction due to reduced TRAF6 ubiquitination.","method":"NF-κB reporter assay, cytokine induction assay, TRAF6 ubiquitination assay with variant IRAK2","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional assays with variant protein plus ubiquitination readout, single lab","pmids":["24973222"],"is_preprint":false},{"year":2021,"finding":"The extreme C-terminal 55 amino acids of IRAK2 (lacking known functional domains) are required for full TRAF6 auto-ubiquitination and optimal TLR4-induced NF-κB and ERK2 activation; the IRAK2Δ55 deletion mutant binds TRAF6 but fails to support TRAF6 auto-ubiquitination as an E3 ligase.","method":"IRAK2 C-terminal deletion mutagenesis, NF-κB and ERK2 activation assays, Co-IP (IRAK2-TRAF6), TRAF6 ubiquitination assay, CD40 expression, IL-6/NO production in macrophages","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — structure-function mutagenesis with multiple downstream readouts, single lab","pmids":["33799071"],"is_preprint":false},{"year":2018,"finding":"IRAK2 phosphorylates Smurf1 at threonine residues to promote Smurf1 self-ubiquitination and degradation in response to ER stress, thereby altering the cascade of ER effectors to induce apoptosis.","method":"Co-immunoprecipitation, phosphorylation assay, ubiquitination assay, overexpression/knockdown in colorectal cancer cells","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single set of assays, no in vitro reconstitution or structural validation","pmids":["29753111"],"is_preprint":false},{"year":2021,"finding":"IRAK2 overexpression enhances radiosensitivity of oral squamous cell carcinoma cells by enhancing ionizing radiation-induced caspase-8/3-dependent apoptosis; low IRAK2 expression correlates with radioresistant phenotype.","method":"IRAK2 overexpression and knockdown in OSCC cell lines, clonogenic survival assay, caspase-8/3 activity assay, in vivo xenograft model","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional assay with pathway readout but no direct biochemical mechanism established for IRAK2-caspase link, single lab","pmids":["34249686"],"is_preprint":false},{"year":2023,"finding":"Adipsin directly interacts with IRAK2 (shown by LC-MS/MS, GST pull-down, Co-IP, immunofluorescence co-localization) and inhibits IRAK2 mitochondrial translocation in diabetic cardiomyopathy, thereby preventing IRAK2 interaction with PHB/OPA1 and preserving mitochondrial structure and fatty acid β-oxidation. Irak2 knockdown abolished the protective effects of Adipsin overexpression.","method":"LC-MS/MS interactome, GST pull-down, Co-IP, immunofluorescence co-localization, immunocolloidal gold electron microscopy, Western blot, IRAK2 knockdown epistasis, high-fat diet mouse model","journal":"Military Medical Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding methods plus epistasis experiment, single lab","pmids":["38072993"],"is_preprint":false},{"year":2026,"finding":"Loss-of-function mutation (IRAK2-Δex2, skipping exon 2) disrupts IRAK2 interaction with IRAK4, impairing Myddosome assembly, NF-κB and MAPK activation; IRAK2 deficiency leads to upregulated type I interferon responses via engagement of a TRIF-dependent interferon pathway in macrophages; Baricitinib attenuates elevated IFN signature in patient-derived cells.","method":"Patient loss-of-function variant characterization, Co-IP (IRAK2-IRAK4 interaction), NF-κB/MAPK signaling assays, IRAK2 knockout cell lines, knock-in mouse BMDMs, IFN signature analysis, baricitinib rescue experiment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — human patients plus knock-in mice plus knockout cell lines plus multiple signaling assays and pharmacological rescue, orthogonal methods, published in Nature Communications","pmids":["42168171"],"is_preprint":false},{"year":2025,"finding":"PELI1 (an E3 ubiquitin ligase) induces K63-linked ubiquitination and protein degradation of IRAK2; IRAK2 overexpression activates p38 MAPK/NF-κB signaling to exacerbate airway inflammation; PELI1-mediated IRAK2 degradation mitigates HDM-induced airway inflammation in pediatric asthma models.","method":"AAV6.2-mediated Peli1 overexpression in airway epithelium, CRISPR/Cas9 PELI1 knockout, ubiquitination assays (K63 linkage), Western blot, NF-κB/MAPK pathway analysis, HDM mouse model","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — K63-ubiquitination assay and epistasis with IRAK2 rescue experiment, single lab","pmids":["40986758"],"is_preprint":false},{"year":2024,"finding":"Novel IRAK2 mutations in patients with severe invasive infections compromise IRAK2's capacity to ubiquitinate TRAF6, resulting in impaired TNF-α production.","method":"Patient variant characterization, TRAF6 ubiquitination assay","journal":"International journal of infectious diseases","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single clinical report with ubiquitination assay, limited mechanistic depth","pmids":["39299377"],"is_preprint":false},{"year":2009,"finding":"miR-146a targets IRAK2 (in addition to TRAF6 and IRAK1) in macrophages, and IRAK1/IRAK2 participate in VSV-induced type I IFN production by associating with FADD (Fas-associated death domain protein) in a VSV infection-inducible manner.","method":"miRNA target validation, Co-IP (IRAK1/IRAK2 with FADD), VSV infection assay, IFN production measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP of IRAK2-FADD association plus functional knockdown, single lab, two methods","pmids":["19596990"],"is_preprint":false},{"year":2018,"finding":"Small molecule mimetics of the α-helical domain of IRAK2 competitively disrupt the IRAK2-IRAK4 protein-protein interaction within the Myddosome, inhibiting IL-33-induced NF-κB activity and attenuating airway inflammation in mouse asthma models.","method":"NF-κB promoter assay (compound screening), protein-protein interaction disruption assay (Myddosome), in vivo IL-33-induced and OVA-induced mouse asthma models","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — PPI disruption confirmed functionally with in vivo validation, single lab","pmids":["29728508"],"is_preprint":false}],"current_model":"IRAK2 is a pseudokinase-like death domain-containing signaling adapter that is recruited to the MyD88-IRAK4-IRAK2 Myddosome helical complex (6:4:4 stoichiometry) downstream of TLR/IL-1R engagement, where it promotes TRAF6 K63-linked ubiquitination to sustain late-phase NF-κB activation and cytokine production; it undergoes sumoylation and nuclear translocation to phosphorylate SRSF1 and facilitate nuclear export of inflammatory mRNAs; it also translocates to mitochondria in response to IL-1 where it interacts with PHB1 and OPA1 to suppress respiratory super-complex formation and oxidative metabolism, and can be degraded via PELI1-mediated K63 ubiquitination to limit inflammatory signaling."},"narrative":{"mechanistic_narrative":"IRAK2 is a death domain-containing signaling adapter that drives Toll-like receptor (TLR) and IL-1 receptor (IL-1R)–induced inflammatory gene expression by nucleating and sustaining the downstream signaling complex [PMID:9374458, PMID:18438411]. It assembles into the Myddosome, a left-handed helical oligomer of six MyD88, four IRAK4, and four IRAK2 death domains in which MyD88 recruits IRAK4 and IRAK4 in turn recruits IRAK2 [PMID:20485341, PMID:42168171]. Functionally, IRAK2 acts downstream of MyD88/Mal but upstream of TRIF and is required across multiple TLRs (TLR2/3/4/5/7/8/9) to promote TRAF6 K63-linked ubiquitination, the critical step for NF-κB activation [PMID:17878161]. Whereas IRAK1 activity declines rapidly, IRAK2 specifically sustains the late phase of NF-κB activation, IKKβ activity, and cytokine output, such that cytokine production is only abolished when both IRAK1 and IRAK2 are lost [PMID:18438411, PMID:23918981]. The IRAK2–TRAF6 interaction (via residue E525) and the extreme C-terminus are required to support TRAF6 auto-ubiquitination and full late-phase cytokine and ERK signaling [PMID:23918981, PMID:33799071]. Beyond the cytoplasmic signaling complex, IRAK2 phosphorylates SRSF1 in the nucleus after LPS stimulation to promote nuclear export of a subset of inflammatory mRNAs following RanBP2-dependent sumoylation [PMID:28990926], and it translocates to mitochondria upon IL-1 stimulation where it binds PHB1 and OPA1 to suppress respiratory super-complex formation and oxidative metabolism [PMID:32778760]. IRAK2 signaling is restrained by PELI1-mediated K63-linked ubiquitination and degradation [PMID:40986758]. Human loss-of-function IRAK2 variants impair TRAF6 ubiquitination and cytokine induction and disrupt Myddosome assembly, causing impaired NF-κB/MAPK signaling with a paradoxical type I interferon signature and susceptibility to severe infection [PMID:26250868, PMID:42168171].","teleology":[{"year":1997,"claim":"Established IRAK2 as a proximal IL-1R signaling component, answering whether it physically engages the receptor complex and contributes to NF-κB activation.","evidence":"Co-IP and dominant-negative overexpression with NF-κB reporters in the IL-1R complex","pmids":["9374458"],"confidence":"High","gaps":["Did not resolve stoichiometry or hierarchy of complex assembly","Did not define the biochemical step IRAK2 catalyzes"]},{"year":2007,"claim":"Defined the core biochemical output of IRAK2 by showing it, not IRAK1, drives TRAF6 K63-linked ubiquitination required for NF-κB activation across most TLRs.","evidence":"siRNA knockdown, loss-of-function mutants, TRAF6 ubiquitination and NF-κB reporter assays in human cells","pmids":["17878161"],"confidence":"High","gaps":["Did not establish whether IRAK2 acts as kinase, scaffold, or E3 cofactor in promoting ubiquitination"]},{"year":2008,"claim":"Resolved the temporal division of labor between IRAK1 and IRAK2, showing IRAK2 sustains late-phase NF-κB and cytokine output.","evidence":"IRAK1/IRAK2 knockout mouse macrophages with kinase activity and cytokine assays","pmids":["18438411"],"confidence":"High","gaps":["Did not define the substrate of sustained IRAK2 kinase activity","Mechanism of late-phase specificity left open"]},{"year":2010,"claim":"Provided the structural basis for Myddosome assembly, defining IRAK2's 6:4:4 stoichiometry and hierarchical recruitment by IRAK4.","evidence":"X-ray crystallography of MyD88-IRAK4-IRAK2 death domains with mutagenesis","pmids":["20485341"],"confidence":"High","gaps":["Did not capture full-length kinase domains or downstream signaling complexes","Order of kinase activation events inferred from proximity"]},{"year":2013,"claim":"Pinpointed the IRAK2-TRAF6 interaction (E525) as the determinant of late-phase but not early-phase cytokine production.","evidence":"IRAK2[E525A] knock-in mice with BMDM and pDC cytokine and IKKβ activity assays","pmids":["23918981"],"confidence":"High","gaps":["Did not address non-TRAF6 IRAK2 functions","Cell-type differences in IFN dependence not fully explained"]},{"year":2017,"claim":"Revealed an unexpected nuclear function in which IRAK2 controls export of inflammatory mRNAs via SRSF1 phosphorylation.","evidence":"Nuclear fractionation, sumoylation assays, in vitro SRSF1 phosphorylation, mRNA export assays in murine macrophages","pmids":["28990926"],"confidence":"High","gaps":["Catalytic competence of IRAK2 as a protein kinase not biochemically reconciled with prior pseudokinase data","Generality across cell types untested"]},{"year":2020,"claim":"Identified a mitochondrial role linking IRAK2 to metabolic suppression, distinct from its NF-κB signaling function.","evidence":"Mitochondrial fractionation, Co-IP with TOM20/TIMM50/PHB1/OPA1, conditional KO and kinase-dead knock-in mice, Seahorse assays","pmids":["32778760"],"confidence":"High","gaps":["Mechanism by which IRAK2 disrupts super-complexes molecularly undefined","Switch between signaling and mitochondrial pools unresolved"]},{"year":2021,"claim":"Mapped a C-terminal element required for IRAK2 to support TRAF6 auto-ubiquitination independent of TRAF6 binding.","evidence":"C-terminal deletion mutagenesis with NF-κB/ERK2 and TRAF6 ubiquitination assays in macrophages","pmids":["33799071"],"confidence":"Medium","gaps":["Molecular partner engaged by the C-terminal 55 residues not identified","Single lab, no structural validation"]},{"year":2025,"claim":"Established a negative-regulatory mechanism by which PELI1 ubiquitinates and degrades IRAK2 to limit inflammation.","evidence":"Peli1 overexpression/knockout, K63-ubiquitination assays and IRAK2 rescue in airway inflammation models","pmids":["40986758"],"confidence":"Medium","gaps":["Single lab","Ubiquitination linkage-to-degradation coupling not fully dissected"]},{"year":2026,"claim":"Linked IRAK2 loss-of-function in patients to disrupted Myddosome assembly and a paradoxical type I interferon phenotype, defining a human disease connection.","evidence":"Patient variant characterization, Co-IP, signaling assays, knockout cells and knock-in mouse BMDMs with baricitinib rescue","pmids":["42168171"],"confidence":"High","gaps":["Mechanism redirecting signaling to TRIF-dependent IFN not fully resolved","Penetrance and clinical spectrum incompletely defined"]},{"year":null,"claim":"It remains unresolved whether IRAK2 functions as a catalytically active kinase or scaffold across its cytoplasmic, nuclear, and mitochondrial roles, and how a single protein is partitioned among these distinct compartments.","evidence":"Conflicting reports of negligible autophosphorylation versus required kinase activity for sumoylation/SRSF1 phosphorylation","pmids":[],"confidence":"Medium","gaps":["No unified structural/biochemical model of IRAK2 catalysis","Regulation of subcellular pool selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5,19]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[7]}],"complexes":["Myddosome (MyD88-IRAK4-IRAK2)"],"partners":["MYD88","IRAK4","TRAF6","PHB1","OPA1","PELI1","SRSF1","FADD"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43187","full_name":"Interleukin-1 receptor-associated kinase-like 2","aliases":[],"length_aa":625,"mass_kda":69.4,"function":"Binds to the IL-1 type I receptor following IL-1 engagement, triggering intracellular signaling cascades leading to transcriptional up-regulation and mRNA stabilization","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O43187/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IRAK2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IRAK2","total_profiled":1310},"omim":[{"mim_id":"608321","title":"TIR DOMAIN-CONTAINING ADAPTOR MOLECULE 2; TICAM2","url":"https://www.omim.org/entry/608321"},{"mim_id":"607601","title":"TIR DOMAIN-CONTAINING ADAPTOR MOLECULE 1; TICAM1","url":"https://www.omim.org/entry/607601"},{"mim_id":"606883","title":"INTERLEUKIN 1 RECEPTOR-ASSOCIATED KINASE 4; IRAK4","url":"https://www.omim.org/entry/606883"},{"mim_id":"606252","title":"TIR DOMAIN-CONTAINING ADAPTOR PROTEIN; TIRAP","url":"https://www.omim.org/entry/606252"},{"mim_id":"604459","title":"INTERLEUKIN 1 RECEPTOR-ASSOCIATED KINASE 3; IRAK3","url":"https://www.omim.org/entry/604459"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":21.9}],"url":"https://www.proteinatlas.org/search/IRAK2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O43187","domains":[{"cath_id":"1.10.533.10","chopping":"6-93","consensus_level":"high","plddt":84.9426,"start":6,"end":93},{"cath_id":"3.30.200.20","chopping":"194-288","consensus_level":"high","plddt":83.7419,"start":194,"end":288},{"cath_id":"1.10.510.10","chopping":"293-433_446-508","consensus_level":"high","plddt":82.4516,"start":293,"end":508}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43187","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43187-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43187-F1-predicted_aligned_error_v6.png","plddt_mean":67.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IRAK2","jax_strain_url":"https://www.jax.org/strain/search?query=IRAK2"},"sequence":{"accession":"O43187","fasta_url":"https://rest.uniprot.org/uniprotkb/O43187.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43187/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43187"}},"corpus_meta":[{"pmid":"9374458","id":"PMC_9374458","title":"IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling.","date":"1997","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9374458","citation_count":944,"is_preprint":false},{"pmid":"20485341","id":"PMC_20485341","title":"Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling.","date":"2010","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/20485341","citation_count":883,"is_preprint":false},{"pmid":"19596990","id":"PMC_19596990","title":"MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19596990","citation_count":627,"is_preprint":false},{"pmid":"18438411","id":"PMC_18438411","title":"Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2.","date":"2008","source":"Nature 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\"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP of complex formation plus dominant-negative functional validation, foundational paper replicated extensively by subsequent work\",\n      \"pmids\": [\"9374458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of the MyD88-IRAK4-IRAK2 death domain (Myddosome) complex reveals a left-handed helical oligomer of 6 MyD88, 4 IRAK4, and 4 IRAK2 DDs; assembly is hierarchical (MyD88 recruits IRAK4, then IRAK4 recruits IRAK2/IRAK1); composite binding sites are required, confirmed by mutagenesis; proximity of kinase domains enables phosphorylation/activation.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, functional signaling assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validation, published in Nature, widely replicated\",\n      \"pmids\": [\"20485341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IRAK2 is essential for sustaining late-phase (peaking ~8 h) TLR-induced NF-κB activation and cytokine gene expression downstream of IRAK4; its kinase activity is sustained whereas IRAK1 kinase activity and protein levels decline within 1 h. TLR-induced cytokine production is abolished only in cells lacking both IRAK1 and IRAK2.\",\n      \"method\": \"IRAK1/IRAK2 knockout mouse macrophages, kinase activity assays, cytokine production measurements, NF-κB reporter assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout in primary immune cells with multiple orthogonal phenotypic readouts, replicated in subsequent knock-in studies\",\n      \"pmids\": [\"18438411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IRAK-2 is critical for TLR-mediated NF-κB activation across multiple TLRs (TLR2, 3, 4, 5, 7, 8, 9); IRAK-2 acts downstream of MyD88/Mal but upstream of TRIF; expression of IRAK-2 (but not IRAK-1) drives TRAF6 K63-linked ubiquitination, a critical step for NF-κB activation; loss-of-function IRAK-2 mutants that cannot activate NF-κB also fail to promote TRAF6 ubiquitination.\",\n      \"method\": \"siRNA knockdown in human cell lines and primary cells, overexpression assays, TRAF6 ubiquitination assay, NF-κB reporter assay, poxviral antagonist A52 interaction studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple TLRs tested, primary human cells, loss-of-function mutants linked mechanistically to TRAF6 ubiquitination, replicated in other labs\",\n      \"pmids\": [\"17878161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The IRAK2-TRAF6 interaction (via IRAK2 E525) is required for the late phase (2–8 h) but not early phase (0–2 h) of IL-6 and TNF-α mRNA production and secretion in bone marrow-derived macrophages stimulated via MyD88-dependent TLRs; the IRAK2-TRAF6 interaction sustains IKKβ activity during prolonged MyD88 network activation; in plasmacytoid dendritic cells, IRAK2-TRAF6 interaction is needed for IFN-α (but not IFN-β) production.\",\n      \"method\": \"IRAK2[E525A] and IRAK1[D359A] knock-in mice, BMDM and pDC cytokine assays, IKKβ activity assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mice with precise mutation at TRAF6-binding site, multiple cell types and cytokine readouts, rigorous controls\",\n      \"pmids\": [\"23918981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-1 induces IRAK2 Myddosome recruitment to mitochondrial outer membranes via TOM20 recognition, followed by TIMM50-guided translocation into mitochondrial inner membranes; mitochondrial IRAK2 suppresses oxidative phosphorylation and fatty acid oxidation by interacting with PHB1 and OPA1, thereby disrupting respiratory super-complex formation. Adipocyte-specific MyD88 or IRAK2 deficiency reduces high-fat diet-induced weight gain and improves insulin resistance.\",\n      \"method\": \"Mitochondrial fractionation, co-immunoprecipitation (IRAK2 with TOM20, TIMM50, PHB1, OPA1), adipocyte-specific conditional KO mice, IRAK2 kinase-inactive knockin mice, metabolic phenotyping, Seahorse assay\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (fractionation, Co-IP, conditional KO, kinase-dead knockin) in single rigorous study published in Nature immunology\",\n      \"pmids\": [\"32778760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LPS/TLR4 engagement promotes nuclear localization of IRAK2; IRAK2 kinase activity is required for RanBP2-mediated IRAK2 sumoylation and subsequent nuclear translocation; nuclear IRAK2 phosphorylates SRSF1 to reduce its binding to target mRNAs, promoting ALYREF binding and Nxf1 loading for nuclear export of a specific subset of inflammatory mRNAs (enriched for SRSF1-binding motifs) in murine macrophages.\",\n      \"method\": \"Nuclear fractionation/localization assays, IRAK2 kinase mutant analysis, sumoylation assays, RNA-binding and nuclear export assays, mRNA array analysis, phosphorylation of SRSF1 in vitro\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (fractionation, sumoylation, SRSF1 phosphorylation, mRNA export assay) in a single study; novel mechanism\",\n      \"pmids\": [\"28990926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IRAK2 contributes to ER stress-mediated unfolded protein response signaling specifically through the IRE1 pathway; knockdown of IRAK2 suppresses ER stress-induced CHOP expression and stress kinase activation; ER stress induces IRAK2 gene expression in an IRE1/XBP1-dependent manner, creating a positive amplification loop; Irak2 knockout mice show defects in ER stress-induced CHOP expression and IRE1 signaling.\",\n      \"method\": \"siRNA kinome screen, RNAi knockdown in mammalian and Drosophila cells, Irak2 knockout mice, ER stress induction assays, UPR pathway analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mice plus cell-based pathway analysis, but single lab and no reconstitution/structural validation\",\n      \"pmids\": [\"23724040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The murine Irak2 gene encodes four alternatively spliced isoforms (Irak2a–d); Irak2a and Irak2b (containing intact death domain) potentiate NF-κB activation; Irak2c and Irak2d are inhibitory; LPS induces Irak2c expression via an NF-κB-responsive promoter, suggesting a negative feedback mechanism. No equivalent alternative splicing was found for human IRAK2.\",\n      \"method\": \"Molecular cloning, alternative splicing analysis, NF-κB reporter overexpression assays, LPS stimulation, promoter analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — molecular cloning with functional overexpression assays and promoter analysis, single lab\",\n      \"pmids\": [\"15082713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Murine IRAK-2 shares 67% sequence identity with human IRAK-2, is ubiquitously expressed, and both murine and human forms practically lack autophosphorylation kinase activity; unlike human IRAK-2, murine IRAK-2 has no stimulatory effect on IL-1-induced NF-κB activation when overexpressed.\",\n      \"method\": \"Molecular cloning, sequence analysis, autophosphorylation kinase assay, NF-κB reporter overexpression assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vitro kinase assay and functional reporter assay; single lab but two orthogonal methods\",\n      \"pmids\": [\"12220507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A deletion in the MOLF/Ei promoter of the inhibitory Irak2c isoform increases the ratio of pro- to anti-inflammatory IRAK-2 isoforms, leading to enhanced early NF-κB activity and p38 MAPK activation in TLR signaling; congenic mapping identified Irak2 as the causative gene at the Why1 locus.\",\n      \"method\": \"Genetic mapping (congenic mice), promoter deletion analysis, NF-κB and MAPK phosphorylation assays, LPS stimulation of primary macrophages\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by congenic mapping combined with biochemical signaling readouts, single lab\",\n      \"pmids\": [\"19564352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Active Ras associates with IRAK, IRAK2, TRAF6, and TAK-1 in the IL-1 signaling complex; dominant-negative RasN17 blocks p38 MAPK activation downstream of TRAF6 but upstream of MKK3/MKK6; Ras likely aids assembly of the IRAK-TRAF6-TAK1 multiprotein complex required for IL-1-induced p38 MAPK activation.\",\n      \"method\": \"Co-immunoprecipitation of active RasVHa with signaling components, dominant-negative transfection epistasis, p38 MAPK activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP plus dominant-negative epistasis, single lab, two orthogonal approaches\",\n      \"pmids\": [\"11744690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IRAK2 and MyD88 (but not IRAK1) physically interact with Akt, as shown by co-immunoprecipitation and pull-down; the IRAK2-Akt association decreases upon IL-1 stimulation and is regulated by PTEN and PDK1; Akt kinase activity is required for IRAK2-dependent (but not IRAK1-dependent) NF-κB transactivation, acting at a step distinct from IκBα dissociation/p65 nuclear translocation.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, NF-κB reporter assay with dominant-negative Akt, iNOS/IL-1β production assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal Co-IP and pull-down plus functional reporter validation, single lab\",\n      \"pmids\": [\"12906710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IRAK-2 mediates pathological Th17 cell development in a CD4 T cell-intrinsic manner by enhancing IL-1β-induced activation of transcription factors RORγt and BATF, as established by adoptive transfer of CD4 T cells from Why1 congenic (Irak2-variant) mice.\",\n      \"method\": \"Adoptive transfer of CD4 T cells, Schistosoma mansoni infection model, RORγt/BATF transcription factor activation assays, congenic mouse genetics\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — adoptive transfer cleanly assigns cell-intrinsic function, supported by transcription factor readouts, single lab\",\n      \"pmids\": [\"21998578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The IRAK2 coding variant L392V (rs3844283) shows intact binding to TRAF6 but impaired TRAF6 ubiquitination, resulting in reduced TLR-mediated cytokine and IFN-α induction in primary plasmacytoid dendritic cells; this hypofunctional variant is associated with reduced spontaneous HCV clearance.\",\n      \"method\": \"Co-immunoprecipitation (IRAK2-TRAF6 binding), ubiquitination assay, primary pDC cytokine/IFN assays, epidemiological cohort analysis\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and ubiquitination assay for mechanism, primary human cells, single lab\",\n      \"pmids\": [\"26250868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The IRAK2 coding variant R214G (rs35060588) is hypofunctional for NF-κB signaling and TLR-mediated cytokine induction due to reduced TRAF6 ubiquitination.\",\n      \"method\": \"NF-κB reporter assay, cytokine induction assay, TRAF6 ubiquitination assay with variant IRAK2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional assays with variant protein plus ubiquitination readout, single lab\",\n      \"pmids\": [\"24973222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The extreme C-terminal 55 amino acids of IRAK2 (lacking known functional domains) are required for full TRAF6 auto-ubiquitination and optimal TLR4-induced NF-κB and ERK2 activation; the IRAK2Δ55 deletion mutant binds TRAF6 but fails to support TRAF6 auto-ubiquitination as an E3 ligase.\",\n      \"method\": \"IRAK2 C-terminal deletion mutagenesis, NF-κB and ERK2 activation assays, Co-IP (IRAK2-TRAF6), TRAF6 ubiquitination assay, CD40 expression, IL-6/NO production in macrophages\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — structure-function mutagenesis with multiple downstream readouts, single lab\",\n      \"pmids\": [\"33799071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IRAK2 phosphorylates Smurf1 at threonine residues to promote Smurf1 self-ubiquitination and degradation in response to ER stress, thereby altering the cascade of ER effectors to induce apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, ubiquitination assay, overexpression/knockdown in colorectal cancer cells\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single set of assays, no in vitro reconstitution or structural validation\",\n      \"pmids\": [\"29753111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IRAK2 overexpression enhances radiosensitivity of oral squamous cell carcinoma cells by enhancing ionizing radiation-induced caspase-8/3-dependent apoptosis; low IRAK2 expression correlates with radioresistant phenotype.\",\n      \"method\": \"IRAK2 overexpression and knockdown in OSCC cell lines, clonogenic survival assay, caspase-8/3 activity assay, in vivo xenograft model\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional assay with pathway readout but no direct biochemical mechanism established for IRAK2-caspase link, single lab\",\n      \"pmids\": [\"34249686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Adipsin directly interacts with IRAK2 (shown by LC-MS/MS, GST pull-down, Co-IP, immunofluorescence co-localization) and inhibits IRAK2 mitochondrial translocation in diabetic cardiomyopathy, thereby preventing IRAK2 interaction with PHB/OPA1 and preserving mitochondrial structure and fatty acid β-oxidation. Irak2 knockdown abolished the protective effects of Adipsin overexpression.\",\n      \"method\": \"LC-MS/MS interactome, GST pull-down, Co-IP, immunofluorescence co-localization, immunocolloidal gold electron microscopy, Western blot, IRAK2 knockdown epistasis, high-fat diet mouse model\",\n      \"journal\": \"Military Medical Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding methods plus epistasis experiment, single lab\",\n      \"pmids\": [\"38072993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Loss-of-function mutation (IRAK2-Δex2, skipping exon 2) disrupts IRAK2 interaction with IRAK4, impairing Myddosome assembly, NF-κB and MAPK activation; IRAK2 deficiency leads to upregulated type I interferon responses via engagement of a TRIF-dependent interferon pathway in macrophages; Baricitinib attenuates elevated IFN signature in patient-derived cells.\",\n      \"method\": \"Patient loss-of-function variant characterization, Co-IP (IRAK2-IRAK4 interaction), NF-κB/MAPK signaling assays, IRAK2 knockout cell lines, knock-in mouse BMDMs, IFN signature analysis, baricitinib rescue experiment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human patients plus knock-in mice plus knockout cell lines plus multiple signaling assays and pharmacological rescue, orthogonal methods, published in Nature Communications\",\n      \"pmids\": [\"42168171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PELI1 (an E3 ubiquitin ligase) induces K63-linked ubiquitination and protein degradation of IRAK2; IRAK2 overexpression activates p38 MAPK/NF-κB signaling to exacerbate airway inflammation; PELI1-mediated IRAK2 degradation mitigates HDM-induced airway inflammation in pediatric asthma models.\",\n      \"method\": \"AAV6.2-mediated Peli1 overexpression in airway epithelium, CRISPR/Cas9 PELI1 knockout, ubiquitination assays (K63 linkage), Western blot, NF-κB/MAPK pathway analysis, HDM mouse model\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — K63-ubiquitination assay and epistasis with IRAK2 rescue experiment, single lab\",\n      \"pmids\": [\"40986758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Novel IRAK2 mutations in patients with severe invasive infections compromise IRAK2's capacity to ubiquitinate TRAF6, resulting in impaired TNF-α production.\",\n      \"method\": \"Patient variant characterization, TRAF6 ubiquitination assay\",\n      \"journal\": \"International journal of infectious diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single clinical report with ubiquitination assay, limited mechanistic depth\",\n      \"pmids\": [\"39299377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"miR-146a targets IRAK2 (in addition to TRAF6 and IRAK1) in macrophages, and IRAK1/IRAK2 participate in VSV-induced type I IFN production by associating with FADD (Fas-associated death domain protein) in a VSV infection-inducible manner.\",\n      \"method\": \"miRNA target validation, Co-IP (IRAK1/IRAK2 with FADD), VSV infection assay, IFN production measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP of IRAK2-FADD association plus functional knockdown, single lab, two methods\",\n      \"pmids\": [\"19596990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Small molecule mimetics of the α-helical domain of IRAK2 competitively disrupt the IRAK2-IRAK4 protein-protein interaction within the Myddosome, inhibiting IL-33-induced NF-κB activity and attenuating airway inflammation in mouse asthma models.\",\n      \"method\": \"NF-κB promoter assay (compound screening), protein-protein interaction disruption assay (Myddosome), in vivo IL-33-induced and OVA-induced mouse asthma models\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — PPI disruption confirmed functionally with in vivo validation, single lab\",\n      \"pmids\": [\"29728508\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IRAK2 is a pseudokinase-like death domain-containing signaling adapter that is recruited to the MyD88-IRAK4-IRAK2 Myddosome helical complex (6:4:4 stoichiometry) downstream of TLR/IL-1R engagement, where it promotes TRAF6 K63-linked ubiquitination to sustain late-phase NF-κB activation and cytokine production; it undergoes sumoylation and nuclear translocation to phosphorylate SRSF1 and facilitate nuclear export of inflammatory mRNAs; it also translocates to mitochondria in response to IL-1 where it interacts with PHB1 and OPA1 to suppress respiratory super-complex formation and oxidative metabolism, and can be degraded via PELI1-mediated K63 ubiquitination to limit inflammatory signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IRAK2 is a death domain-containing signaling adapter that drives Toll-like receptor (TLR) and IL-1 receptor (IL-1R)–induced inflammatory gene expression by nucleating and sustaining the downstream signaling complex [#0, #2]. It assembles into the Myddosome, a left-handed helical oligomer of six MyD88, four IRAK4, and four IRAK2 death domains in which MyD88 recruits IRAK4 and IRAK4 in turn recruits IRAK2 [#1, #20]. Functionally, IRAK2 acts downstream of MyD88/Mal but upstream of TRIF and is required across multiple TLRs (TLR2/3/4/5/7/8/9) to promote TRAF6 K63-linked ubiquitination, the critical step for NF-κB activation [#3]. Whereas IRAK1 activity declines rapidly, IRAK2 specifically sustains the late phase of NF-κB activation, IKKβ activity, and cytokine output, such that cytokine production is only abolished when both IRAK1 and IRAK2 are lost [#2, #4]. The IRAK2–TRAF6 interaction (via residue E525) and the extreme C-terminus are required to support TRAF6 auto-ubiquitination and full late-phase cytokine and ERK signaling [#4, #16]. Beyond the cytoplasmic signaling complex, IRAK2 phosphorylates SRSF1 in the nucleus after LPS stimulation to promote nuclear export of a subset of inflammatory mRNAs following RanBP2-dependent sumoylation [#6], and it translocates to mitochondria upon IL-1 stimulation where it binds PHB1 and OPA1 to suppress respiratory super-complex formation and oxidative metabolism [#5]. IRAK2 signaling is restrained by PELI1-mediated K63-linked ubiquitination and degradation [#21]. Human loss-of-function IRAK2 variants impair TRAF6 ubiquitination and cytokine induction and disrupt Myddosome assembly, causing impaired NF-κB/MAPK signaling with a paradoxical type I interferon signature and susceptibility to severe infection [#14, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established IRAK2 as a proximal IL-1R signaling component, answering whether it physically engages the receptor complex and contributes to NF-κB activation.\",\n      \"evidence\": \"Co-IP and dominant-negative overexpression with NF-κB reporters in the IL-1R complex\",\n      \"pmids\": [\"9374458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve stoichiometry or hierarchy of complex assembly\", \"Did not define the biochemical step IRAK2 catalyzes\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the core biochemical output of IRAK2 by showing it, not IRAK1, drives TRAF6 K63-linked ubiquitination required for NF-κB activation across most TLRs.\",\n      \"evidence\": \"siRNA knockdown, loss-of-function mutants, TRAF6 ubiquitination and NF-κB reporter assays in human cells\",\n      \"pmids\": [\"17878161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether IRAK2 acts as kinase, scaffold, or E3 cofactor in promoting ubiquitination\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the temporal division of labor between IRAK1 and IRAK2, showing IRAK2 sustains late-phase NF-κB and cytokine output.\",\n      \"evidence\": \"IRAK1/IRAK2 knockout mouse macrophages with kinase activity and cytokine assays\",\n      \"pmids\": [\"18438411\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the substrate of sustained IRAK2 kinase activity\", \"Mechanism of late-phase specificity left open\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided the structural basis for Myddosome assembly, defining IRAK2's 6:4:4 stoichiometry and hierarchical recruitment by IRAK4.\",\n      \"evidence\": \"X-ray crystallography of MyD88-IRAK4-IRAK2 death domains with mutagenesis\",\n      \"pmids\": [\"20485341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture full-length kinase domains or downstream signaling complexes\", \"Order of kinase activation events inferred from proximity\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Pinpointed the IRAK2-TRAF6 interaction (E525) as the determinant of late-phase but not early-phase cytokine production.\",\n      \"evidence\": \"IRAK2[E525A] knock-in mice with BMDM and pDC cytokine and IKKβ activity assays\",\n      \"pmids\": [\"23918981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address non-TRAF6 IRAK2 functions\", \"Cell-type differences in IFN dependence not fully explained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed an unexpected nuclear function in which IRAK2 controls export of inflammatory mRNAs via SRSF1 phosphorylation.\",\n      \"evidence\": \"Nuclear fractionation, sumoylation assays, in vitro SRSF1 phosphorylation, mRNA export assays in murine macrophages\",\n      \"pmids\": [\"28990926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic competence of IRAK2 as a protein kinase not biochemically reconciled with prior pseudokinase data\", \"Generality across cell types untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a mitochondrial role linking IRAK2 to metabolic suppression, distinct from its NF-κB signaling function.\",\n      \"evidence\": \"Mitochondrial fractionation, Co-IP with TOM20/TIMM50/PHB1/OPA1, conditional KO and kinase-dead knock-in mice, Seahorse assays\",\n      \"pmids\": [\"32778760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which IRAK2 disrupts super-complexes molecularly undefined\", \"Switch between signaling and mitochondrial pools unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped a C-terminal element required for IRAK2 to support TRAF6 auto-ubiquitination independent of TRAF6 binding.\",\n      \"evidence\": \"C-terminal deletion mutagenesis with NF-κB/ERK2 and TRAF6 ubiquitination assays in macrophages\",\n      \"pmids\": [\"33799071\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partner engaged by the C-terminal 55 residues not identified\", \"Single lab, no structural validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a negative-regulatory mechanism by which PELI1 ubiquitinates and degrades IRAK2 to limit inflammation.\",\n      \"evidence\": \"Peli1 overexpression/knockout, K63-ubiquitination assays and IRAK2 rescue in airway inflammation models\",\n      \"pmids\": [\"40986758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Ubiquitination linkage-to-degradation coupling not fully dissected\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked IRAK2 loss-of-function in patients to disrupted Myddosome assembly and a paradoxical type I interferon phenotype, defining a human disease connection.\",\n      \"evidence\": \"Patient variant characterization, Co-IP, signaling assays, knockout cells and knock-in mouse BMDMs with baricitinib rescue\",\n      \"pmids\": [\"42168171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism redirecting signaling to TRIF-dependent IFN not fully resolved\", \"Penetrance and clinical spectrum incompletely defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether IRAK2 functions as a catalytically active kinase or scaffold across its cytoplasmic, nuclear, and mitochondrial roles, and how a single protein is partitioned among these distinct compartments.\",\n      \"evidence\": \"Conflicting reports of negligible autophosphorylation versus required kinase activity for sumoylation/SRSF1 phosphorylation\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural/biochemical model of IRAK2 catalysis\", \"Regulation of subcellular pool selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\"Myddosome (MyD88-IRAK4-IRAK2)\"],\n    \"partners\": [\"MyD88\", \"IRAK4\", \"TRAF6\", \"PHB1\", \"OPA1\", \"PELI1\", \"SRSF1\", \"FADD\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}