{"gene":"TRAF3IP3","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2003,"finding":"T3JAM (TRAF3IP3) was identified as a novel protein that specifically associates with TRAF3 but not other TRAF family members. Co-expression of T3JAM with TRAF3 recruits TRAF3 to the detergent-insoluble fraction, and T3JAM and TRAF3 synergistically activate JNK but not NF-κB, indicating T3JAM functions as an adapter molecule specifically regulating TRAF3-mediated JNK activation.","method":"Co-immunoprecipitation, subcellular fractionation, overexpression reporter assays for JNK and NF-κB activation","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal specificity shown across TRAF family members, JNK activation confirmed by reporter assay, single lab with multiple orthogonal methods","pmids":["14572659"],"is_preprint":false},{"year":2015,"finding":"TRAF3IP3 localizes to the Golgi and is required for TCR-stimulated ERK and MEK activation during thymocyte positive selection. Mechanistically, TRAF3IP3 recruits MEK to the Golgi, facilitating the interaction of MEK with its activator BRAF. Transgenic expression of constitutively active MEK rescues the T cell development block in Traf3ip3 knockout mice.","method":"Conditional knockout mice, T cell development assays, subcellular fractionation/localization, co-immunoprecipitation, genetic rescue with constitutively active MEK","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with defined phenotype, subcellular localization, co-IP of MEK-BRAF interaction, and genetic rescue with orthogonal transgenic approach","pmids":["26195727"],"is_preprint":false},{"year":2015,"finding":"TRAF3IP3 promotes autophagy via an ATG16L1-binding motif. Loss of TRAF3IP3 in knockout mice leads to diminished autophagy and increased apoptosis in marginal zone B cells, impairing their survival and resulting in defective T-independent type II immune responses.","method":"Knockout mice, autophagy assays, apoptosis assays, mutational analysis of ATG16L1-binding motif","journal":"Clinical and experimental immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with defined cellular phenotype, functional motif identified, single lab","pmids":["26011558"],"is_preprint":false},{"year":2018,"finding":"Lysosomal TRAF3IP3 restricts mTORC1 signaling in regulatory T cells by recruiting the serine-threonine phosphatase catalytic subunit PP2Ac to the lysosome, thereby facilitating the interaction of PP2Ac with the mTORC1 component Raptor. Loss of TRAF3IP3 causes hyper-glycolytic metabolism via excessive mTORC1 activity, destabilizing Treg cells.","method":"T reg-specific conditional knockout mice, co-immunoprecipitation of PP2Ac-Raptor interaction, lysosomal fractionation/localization, metabolic assays, mTORC1 activity measurements","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO, organelle fractionation, co-IP of PP2Ac-Raptor, multiple orthogonal methods in single rigorous study","pmids":["30115741"],"is_preprint":false},{"year":2019,"finding":"TRAF3IP3 accumulates on mitochondria upon virus infection and mediates the recruitment of TRAF3 to MAVS, thereby facilitating TBK1-IRF3 activation for interferon production. Traf3ip3-deficient mice show severely compromised interferon production and increased susceptibility to RNA virus infection.","method":"Knockout mice, virus infection assays, co-immunoprecipitation, mitochondrial localization assays, interferon production measurements","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO, co-IP of TRAF3-MAVS interaction, subcellular localization linked to function, replicated phenotype with multiple orthogonal approaches","pmids":["31390091"],"is_preprint":false},{"year":2019,"finding":"TRAF3IP3 at the trans-Golgi network recruits MEK1 and facilitates ERK phosphorylation and nuclear translocation in NKT2 cells, promoting their functional maturation. T-cell-specific deletion of TRAF3IP3 reduces thymic NKT2 cells and impairs IL-4 production.","method":"T-cell-specific conditional knockout mice, trans-Golgi network localization assays, co-immunoprecipitation of MEK1, ERK phosphorylation and nuclear translocation assays","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with defined cellular phenotype, organelle localization, co-IP, single lab","pmids":["31076725"],"is_preprint":false},{"year":2020,"finding":"TRAF3IP3 suppresses cytosolic RNA-triggered IFN-I production by interacting with endogenous TRAF3 and TBK1, leading to K48-linked (degradative) ubiquitination of TBK1 at its K372 residue in a DTX4-dependent fashion. Myeloid-specific deletion of Traf3ip3 increases RNA virus-triggered IFN-I production and reduces susceptibility to virus.","method":"Myeloid-specific conditional knockout mice, overexpression systems, co-immunoprecipitation of TRAF3 and TBK1, ubiquitination site mapping (K372), DTX4-dependence established by genetic manipulation, virus susceptibility assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO, co-IP, ubiquitination site mapping, genetic epistasis with DTX4, multiple orthogonal methods","pmids":["32366851"],"is_preprint":false},{"year":2022,"finding":"TRAF3IP3 is cleaved by EV71 3C protease at the 87Q-88G site, which partially resists TRAF3IP3-mediated inhibition of EV71 replication. TRAF3IP3 possesses nuclear localization signal (NLS) and nuclear export signal (NES); the NES contributes to TRAF3IP3-mediated alteration of 3Cpro localization and inhibition of EV71 replication.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, cleavage site mapping, NLS/NES functional analysis, viral replication assays in Jurkat and RD cells","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cleavage site mapped, NES function demonstrated, co-IP and immunofluorescence, single lab","pmids":["35814660"],"is_preprint":false},{"year":2024,"finding":"TRAF3IP3 blocks mitophagy to exacerbate myocardial ischemia-reperfusion injury by promoting the degradation of NEDD4 protein. Knockdown of TRAF3IP3 induces mitophagy and enhances mitochondrial function, alleviating myocardial injury in I/R rats.","method":"Co-immunoprecipitation, CHX (cycloheximide chase) assays, immunoblot, immunostaining, knockdown in H9C2 cells, in vivo I/R rat model","journal":"Cardiovascular toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and CHX chase for NEDD4 degradation, in vivo model, single lab with multiple methods","pmids":["39240426"],"is_preprint":false},{"year":2025,"finding":"TRAF3IP3 triggers ER stress via the PERK/ATF4/CHOP pathway in lung adenocarcinoma cells and facilitates recruitment of STRN3 to the ER lumen through its transmembrane domain. TRAF3IP3-induced ER stress-mediated apoptosis and cytoprotective autophagy are dependent on STRN3, identified by IP-MS as a direct downstream interactor.","method":"IP-MS identification of STRN3 as binding partner, co-immunoprecipitation, transmembrane domain mutational analysis, ER stress pathway analysis (PERK/ATF4/CHOP), STRN3 knockdown rescue experiments, cell viability/apoptosis assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS interaction, co-IP, functional dependence on STRN3 and transmembrane domain, single lab","pmids":["40068093"],"is_preprint":false}],"current_model":"TRAF3IP3 (T3JAM) is a multi-compartment adapter protein that localizes to distinct organelles (Golgi, lysosome, mitochondria, ER) to regulate immune signaling: at the Golgi it recruits MEK to facilitate BRAF-MEK-ERK activation during T cell development; at the lysosome it recruits PP2Ac to dephosphorylate the mTORC1 component Raptor and restrain glycolysis in regulatory T cells; on mitochondria it bridges MAVS and TRAF3 to activate TBK1-IRF3-driven interferon production, while also interacting with TBK1 to promote its K48 ubiquitination via DTX4 and limit excess IFN-I in myeloid cells; it promotes autophagy via an ATG16L1-binding motif in B cells; it blocks mitophagy by promoting NEDD4 degradation in cardiomyocytes; and it recruits STRN3 to the ER lumen via its transmembrane domain to drive ER stress-mediated apoptosis in lung adenocarcinoma cells."},"narrative":{"mechanistic_narrative":"TRAF3IP3 (T3JAM) is a multi-compartment adapter protein that couples organelle-specific scaffolding to immune signaling, T cell development, and cell-fate decisions [PMID:26195727, PMID:31390091]. It was first defined as a TRAF3-specific binding partner that recruits TRAF3 to a detergent-insoluble fraction and selectively drives JNK rather than NF-κB activation [PMID:14572659]. In the secretory pathway TRAF3IP3 localizes to the Golgi/trans-Golgi network, where it recruits MEK and promotes its interaction with BRAF to enable TCR-stimulated ERK activation during thymocyte positive selection and NKT2 maturation; a constitutively active MEK transgene rescues the T cell development block in knockout mice [PMID:26195727, PMID:31076725]. At the lysosome it recruits the phosphatase catalytic subunit PP2Ac to engage the mTORC1 component Raptor, thereby restraining mTORC1-driven glycolysis and stabilizing regulatory T cells [PMID:30115741]. In antiviral innate immunity TRAF3IP3 has dual, compartment-dependent roles: it accumulates on mitochondria upon viral infection to bridge TRAF3 to MAVS and license TBK1-IRF3-driven interferon production [PMID:31390091], while also interacting with TRAF3 and TBK1 to direct DTX4-dependent K48-linked ubiquitination of TBK1 at K372, limiting excess type I interferon in myeloid cells [PMID:32366851]. TRAF3IP3 additionally regulates autophagic pathways, promoting autophagy via an ATG16L1-binding motif to sustain marginal zone B cell survival [PMID:26011558] and blocking mitophagy by promoting NEDD4 degradation in cardiomyocytes [PMID:39240426]. Through its transmembrane domain it recruits STRN3 to the ER to trigger PERK/ATF4/CHOP-mediated ER stress and apoptosis in lung adenocarcinoma cells [PMID:40068093].","teleology":[{"year":2003,"claim":"Established TRAF3IP3 as a TRAF-selective adapter, answering whether it engages the TRAF family broadly or specifically and which downstream pathway it routes to.","evidence":"Co-IP across TRAF family members, subcellular fractionation, and JNK/NF-κB reporter assays in overexpression systems","pmids":["14572659"],"confidence":"Medium","gaps":["Endogenous TRAF3 association not shown","Physiological cell context and stimulus undefined","Structural basis of TRAF3 specificity unknown"]},{"year":2015,"claim":"Resolved a developmental function by placing TRAF3IP3 at the Golgi as the scaffold that couples MEK to BRAF for TCR-driven ERK signaling during thymocyte positive selection.","evidence":"Conditional knockout mice, subcellular localization, MEK-BRAF co-IP, and genetic rescue with constitutively active MEK","pmids":["26195727"],"confidence":"High","gaps":["How TRAF3IP3 is targeted to the Golgi not defined","Direct vs. indirect MEK binding interface unmapped"]},{"year":2015,"claim":"Identified an autophagy-promoting role via an ATG16L1-binding motif, linking TRAF3IP3 to marginal zone B cell survival.","evidence":"Knockout mice, autophagy and apoptosis assays, and mutational analysis of the ATG16L1-binding motif","pmids":["26011558"],"confidence":"Medium","gaps":["Direct ATG16L1 binding via the motif not biochemically confirmed","Subcellular site of this interaction undefined"]},{"year":2018,"claim":"Defined a lysosomal, metabolism-restraining function: TRAF3IP3 recruits PP2Ac to dephosphorylate the mTORC1 component Raptor and limit glycolysis in Tregs.","evidence":"Treg-specific conditional knockout, lysosomal fractionation, PP2Ac-Raptor co-IP, and metabolic/mTORC1 activity assays","pmids":["30115741"],"confidence":"High","gaps":["Mechanism of lysosomal targeting unclear","Whether Raptor is the direct PP2Ac dephosphorylation substrate not demonstrated enzymatically"]},{"year":2019,"claim":"Established a positive antiviral role by showing mitochondrial TRAF3IP3 bridges TRAF3 to MAVS to drive TBK1-IRF3 interferon responses.","evidence":"Knockout mice, virus infection assays, TRAF3-MAVS co-IP, and mitochondrial localization linked to IFN output","pmids":["31390091"],"confidence":"High","gaps":["Trigger for mitochondrial accumulation undefined","Direct binding topology among TRAF3IP3/TRAF3/MAVS unmapped"]},{"year":2019,"claim":"Extended the Golgi-MEK-ERK axis to NKT2 cell maturation, generalizing the trans-Golgi scaffolding role beyond conventional thymocytes.","evidence":"T-cell-specific conditional knockout, trans-Golgi localization, MEK1 co-IP, and ERK phosphorylation/nuclear translocation assays","pmids":["31076725"],"confidence":"Medium","gaps":["Single lab","Direct MEK1 binding interface not mapped"]},{"year":2020,"claim":"Revealed an opposing, negative-feedback function in myeloid cells: TRAF3IP3 promotes DTX4-dependent K48 ubiquitination of TBK1 at K372 to restrain excess IFN-I.","evidence":"Myeloid-specific conditional knockout, TRAF3/TBK1 co-IP, ubiquitination site mapping, and DTX4 genetic epistasis","pmids":["32366851"],"confidence":"High","gaps":["How cell-type context switches TRAF3IP3 between pro- and anti-IFN roles unresolved","Whether the same molecular pool performs both functions unknown"]},{"year":2022,"claim":"Characterized TRAF3IP3 as a restriction factor cleaved by enterovirus 3C protease and identified functional NLS/NES elements governing its antiviral activity.","evidence":"Yeast two-hybrid, co-IP, immunofluorescence, cleavage site mapping (87Q-88G), and NLS/NES functional analysis in Jurkat and RD cells","pmids":["35814660"],"confidence":"Medium","gaps":["Nuclear function of TRAF3IP3 not mechanistically defined","Relationship between nuclear shuttling and organelle-based roles unclear"]},{"year":2024,"claim":"Showed TRAF3IP3 blocks mitophagy by promoting NEDD4 degradation, worsening myocardial ischemia-reperfusion injury.","evidence":"Co-IP, cycloheximide chase, knockdown in H9C2 cells, and an in vivo I/R rat model","pmids":["39240426"],"confidence":"Medium","gaps":["Mechanism by which TRAF3IP3 promotes NEDD4 turnover not defined","Link from NEDD4 loss to mitophagy block not fully mapped"]},{"year":2025,"claim":"Identified an ER-localized, pro-apoptotic function: TRAF3IP3 uses its transmembrane domain to recruit STRN3 and trigger PERK/ATF4/CHOP ER stress in lung adenocarcinoma.","evidence":"IP-MS, co-IP, transmembrane domain mutagenesis, STRN3 knockdown rescue, and apoptosis/viability assays","pmids":["40068093"],"confidence":"Medium","gaps":["Direct STRN3 binding interface beyond TM dependence unmapped","How ER targeting is coordinated with other organelle pools unknown"]},{"year":null,"claim":"It remains unresolved how a single adapter is partitioned among Golgi, lysosome, mitochondria, ER, and nucleus, and what governs its context-dependent switching between opposing functions (pro- vs. anti-interferon; autophagy vs. mitophagy).","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model defines distinct organelle-targeting determinants","No single study compares multiple compartmental pools in one cell type","Direct binding interfaces for most partners (MEK, MAVS, PP2Ac, STRN3) unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,6]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[3]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,4,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,5]}],"complexes":[],"partners":["TRAF3","MEK1","BRAF","MAVS","TBK1","PP2AC","ATG16L1","STRN3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y228","full_name":"TRAF3-interacting JNK-activating modulator","aliases":["TRAF3-interacting protein 3"],"length_aa":551,"mass_kda":63.6,"function":"Adapter protein that plays essential roles in both innate and adaptive immunity. Plays a crucial role in the regulation of thymocyte development (PubMed:26195727). Mechanistically, mediates TCR-stimulated activation through recruiting MAP2K1/MEK1 to the Golgi and, thereby, facilitating the interaction of MAP2K1/MEK1 with its activator BRAF (PubMed:26195727). Also plays an essential role in regulatory T-cell stability and function by recruiting the serine-threonine phosphatase catalytic subunit (PPP2CA) to the lysosome, thereby facilitating the interaction of PP2Ac with the mTORC1 component RPTOR and restricting glycolytic metabolism (PubMed:30115741). Positively regulates TLR4 signaling activity in macrophage-mediated inflammation by acting as a molecular clamp to facilitate LPS-induced translocation of TLR4 to lipid rafts (PubMed:30573680). In response to viral infection, facilitates the recruitment of TRAF3 to MAVS within mitochondria leading to IRF3 activation and interferon production (PubMed:31390091). However, participates in the maintenance of immune homeostasis and the prevention of overzealous innate immunity by promoting 'Lys-48'-dependent ubiquitination of TBK1 (PubMed:32366851)","subcellular_location":"Cell membrane; Golgi apparatus membrane; Lysosome membrane; Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y228/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRAF3IP3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRAF3IP3","total_profiled":1310},"omim":[{"mim_id":"610767","title":"AUTOPHAGY 16-LIKE 1; ATG16L1","url":"https://www.omim.org/entry/610767"},{"mim_id":"608255","title":"TRAF3-INTERACTING PROTEIN 3; TRAF3IP3","url":"https://www.omim.org/entry/608255"},{"mim_id":"607502","title":"DISPATCHED RND TRANSPORTER FAMILY, MEMBER 1; DISP1","url":"https://www.omim.org/entry/607502"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":121.5}],"url":"https://www.proteinatlas.org/search/TRAF3IP3"},"hgnc":{"alias_symbol":["T3JAM"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y228","domains":[{"cath_id":"1.20.5","chopping":"297-417","consensus_level":"medium","plddt":96.902,"start":297,"end":417}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y228","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y228-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y228-F1-predicted_aligned_error_v6.png","plddt_mean":74.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRAF3IP3","jax_strain_url":"https://www.jax.org/strain/search?query=TRAF3IP3"},"sequence":{"accession":"Q9Y228","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y228.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y228/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y228"}},"corpus_meta":[{"pmid":"30115741","id":"PMC_30115741","title":"Metabolic control of regulatory T cell stability and function by TRAF3IP3 at the lysosome.","date":"2018","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30115741","citation_count":60,"is_preprint":false},{"pmid":"32366851","id":"PMC_32366851","title":"TRAF3IP3 negatively regulates cytosolic RNA induced anti-viral signaling by promoting TBK1 K48 ubiquitination.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32366851","citation_count":48,"is_preprint":false},{"pmid":"31390091","id":"PMC_31390091","title":"TRAF3IP3 mediates the recruitment of TRAF3 to MAVS for antiviral innate immunity.","date":"2019","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/31390091","citation_count":46,"is_preprint":false},{"pmid":"14572659","id":"PMC_14572659","title":"T3JAM, a novel protein that specifically interacts with TRAF3 and promotes the activation of JNK(1).","date":"2003","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/14572659","citation_count":38,"is_preprint":false},{"pmid":"26195727","id":"PMC_26195727","title":"T cell development involves TRAF3IP3-mediated ERK signaling in the Golgi.","date":"2015","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26195727","citation_count":37,"is_preprint":false},{"pmid":"26011558","id":"PMC_26011558","title":"TRAF3IP3, a novel autophagy up-regulated gene, is involved in marginal zone B lymphocyte development and survival.","date":"2015","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26011558","citation_count":29,"is_preprint":false},{"pmid":"34419138","id":"PMC_34419138","title":"Alpinia oxyphylla Miq extract reduces cerebral infarction by downregulating JNK-mediated TLR4/T3JAM- and ASK1-related inflammatory signaling in the acute phase of transient focal cerebral ischemia in rats.","date":"2021","source":"Chinese medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34419138","citation_count":14,"is_preprint":false},{"pmid":"35814660","id":"PMC_35814660","title":"TRAF3IP3 Is Cleaved by EV71 3C Protease and Exhibits Antiviral Activity.","date":"2022","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35814660","citation_count":12,"is_preprint":false},{"pmid":"31076725","id":"PMC_31076725","title":"TRAF3IP3 at the trans-Golgi network regulates NKT2 maturation via the MEK/ERK signaling pathway.","date":"2019","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31076725","citation_count":10,"is_preprint":false},{"pmid":"40068093","id":"PMC_40068093","title":"TRAF3IP3 Induces ER Stress-Mediated Apoptosis with Protective Autophagy to Inhibit Lung Adenocarcinoma Proliferation.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40068093","citation_count":9,"is_preprint":false},{"pmid":"39391701","id":"PMC_39391701","title":"Neuroprotective effects of Gastrodia elata Blume on promoting M2 microglial polarization by inhibiting JNK/TLR4/T3JAM/NF-κB signaling after transient ischemic stroke in rats.","date":"2024","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39391701","citation_count":8,"is_preprint":false},{"pmid":"36185204","id":"PMC_36185204","title":"TRAF3IP3 promotes glioma progression through the ERK signaling pathway.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36185204","citation_count":7,"is_preprint":false},{"pmid":"33503336","id":"PMC_33503336","title":"Novel germline TRAF3IP3 mutation in a dyad with familial acute B lymphoblastic leukemia.","date":"2021","source":"Cancer reports (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/33503336","citation_count":6,"is_preprint":false},{"pmid":"39240426","id":"PMC_39240426","title":"TRAF3IP3 Blocks Mitophagy to Exacerbate Myocardial Injury Induced by Ischemia-Reperfusion.","date":"2024","source":"Cardiovascular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/39240426","citation_count":3,"is_preprint":false},{"pmid":"39166607","id":"PMC_39166607","title":"SNORA5A regulates tumor-associated macrophage M1/M2 phenotypes via TRAF3IP3 in breast cancer.","date":"2024","source":"Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas","url":"https://pubmed.ncbi.nlm.nih.gov/39166607","citation_count":3,"is_preprint":false},{"pmid":"36397361","id":"PMC_36397361","title":"The variants in PTPRB, TRAF3IP3, and DISC1 genes were associated with Graves' disease in the Chinese population.","date":"2022","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36397361","citation_count":1,"is_preprint":false},{"pmid":"23643262","id":"PMC_23643262","title":"[Cloning and eukaryotic expression of human TRAF3IP3 gene].","date":"2013","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23643262","citation_count":1,"is_preprint":false},{"pmid":"39581339","id":"PMC_39581339","title":"Targeting inhibition of T3JAM reduces brain cell ferroptosis in rat following ischemia/reperfusion via a mechanism involving prevention of TLR4-mediated iron overload.","date":"2024","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/39581339","citation_count":0,"is_preprint":false},{"pmid":"40590913","id":"PMC_40590913","title":"TRAF3IP3::FGFR1: a novel FGFR1 fusion identified in an aggressive case of acute myeloid leukemia.","date":"2025","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/40590913","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12039,"output_tokens":2859,"usd":0.039501,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10120,"output_tokens":3793,"usd":0.072712,"stage2_stop_reason":"end_turn"},"total_usd":0.112213,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"T3JAM (TRAF3IP3) was identified as a novel protein that specifically associates with TRAF3 but not other TRAF family members. Co-expression of T3JAM with TRAF3 recruits TRAF3 to the detergent-insoluble fraction, and T3JAM and TRAF3 synergistically activate JNK but not NF-κB, indicating T3JAM functions as an adapter molecule specifically regulating TRAF3-mediated JNK activation.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, overexpression reporter assays for JNK and NF-κB activation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal specificity shown across TRAF family members, JNK activation confirmed by reporter assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"14572659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRAF3IP3 localizes to the Golgi and is required for TCR-stimulated ERK and MEK activation during thymocyte positive selection. Mechanistically, TRAF3IP3 recruits MEK to the Golgi, facilitating the interaction of MEK with its activator BRAF. Transgenic expression of constitutively active MEK rescues the T cell development block in Traf3ip3 knockout mice.\",\n      \"method\": \"Conditional knockout mice, T cell development assays, subcellular fractionation/localization, co-immunoprecipitation, genetic rescue with constitutively active MEK\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with defined phenotype, subcellular localization, co-IP of MEK-BRAF interaction, and genetic rescue with orthogonal transgenic approach\",\n      \"pmids\": [\"26195727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRAF3IP3 promotes autophagy via an ATG16L1-binding motif. Loss of TRAF3IP3 in knockout mice leads to diminished autophagy and increased apoptosis in marginal zone B cells, impairing their survival and resulting in defective T-independent type II immune responses.\",\n      \"method\": \"Knockout mice, autophagy assays, apoptosis assays, mutational analysis of ATG16L1-binding motif\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with defined cellular phenotype, functional motif identified, single lab\",\n      \"pmids\": [\"26011558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Lysosomal TRAF3IP3 restricts mTORC1 signaling in regulatory T cells by recruiting the serine-threonine phosphatase catalytic subunit PP2Ac to the lysosome, thereby facilitating the interaction of PP2Ac with the mTORC1 component Raptor. Loss of TRAF3IP3 causes hyper-glycolytic metabolism via excessive mTORC1 activity, destabilizing Treg cells.\",\n      \"method\": \"T reg-specific conditional knockout mice, co-immunoprecipitation of PP2Ac-Raptor interaction, lysosomal fractionation/localization, metabolic assays, mTORC1 activity measurements\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO, organelle fractionation, co-IP of PP2Ac-Raptor, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"30115741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRAF3IP3 accumulates on mitochondria upon virus infection and mediates the recruitment of TRAF3 to MAVS, thereby facilitating TBK1-IRF3 activation for interferon production. Traf3ip3-deficient mice show severely compromised interferon production and increased susceptibility to RNA virus infection.\",\n      \"method\": \"Knockout mice, virus infection assays, co-immunoprecipitation, mitochondrial localization assays, interferon production measurements\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO, co-IP of TRAF3-MAVS interaction, subcellular localization linked to function, replicated phenotype with multiple orthogonal approaches\",\n      \"pmids\": [\"31390091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRAF3IP3 at the trans-Golgi network recruits MEK1 and facilitates ERK phosphorylation and nuclear translocation in NKT2 cells, promoting their functional maturation. T-cell-specific deletion of TRAF3IP3 reduces thymic NKT2 cells and impairs IL-4 production.\",\n      \"method\": \"T-cell-specific conditional knockout mice, trans-Golgi network localization assays, co-immunoprecipitation of MEK1, ERK phosphorylation and nuclear translocation assays\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with defined cellular phenotype, organelle localization, co-IP, single lab\",\n      \"pmids\": [\"31076725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRAF3IP3 suppresses cytosolic RNA-triggered IFN-I production by interacting with endogenous TRAF3 and TBK1, leading to K48-linked (degradative) ubiquitination of TBK1 at its K372 residue in a DTX4-dependent fashion. Myeloid-specific deletion of Traf3ip3 increases RNA virus-triggered IFN-I production and reduces susceptibility to virus.\",\n      \"method\": \"Myeloid-specific conditional knockout mice, overexpression systems, co-immunoprecipitation of TRAF3 and TBK1, ubiquitination site mapping (K372), DTX4-dependence established by genetic manipulation, virus susceptibility assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO, co-IP, ubiquitination site mapping, genetic epistasis with DTX4, multiple orthogonal methods\",\n      \"pmids\": [\"32366851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRAF3IP3 is cleaved by EV71 3C protease at the 87Q-88G site, which partially resists TRAF3IP3-mediated inhibition of EV71 replication. TRAF3IP3 possesses nuclear localization signal (NLS) and nuclear export signal (NES); the NES contributes to TRAF3IP3-mediated alteration of 3Cpro localization and inhibition of EV71 replication.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, cleavage site mapping, NLS/NES functional analysis, viral replication assays in Jurkat and RD cells\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cleavage site mapped, NES function demonstrated, co-IP and immunofluorescence, single lab\",\n      \"pmids\": [\"35814660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRAF3IP3 blocks mitophagy to exacerbate myocardial ischemia-reperfusion injury by promoting the degradation of NEDD4 protein. Knockdown of TRAF3IP3 induces mitophagy and enhances mitochondrial function, alleviating myocardial injury in I/R rats.\",\n      \"method\": \"Co-immunoprecipitation, CHX (cycloheximide chase) assays, immunoblot, immunostaining, knockdown in H9C2 cells, in vivo I/R rat model\",\n      \"journal\": \"Cardiovascular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and CHX chase for NEDD4 degradation, in vivo model, single lab with multiple methods\",\n      \"pmids\": [\"39240426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRAF3IP3 triggers ER stress via the PERK/ATF4/CHOP pathway in lung adenocarcinoma cells and facilitates recruitment of STRN3 to the ER lumen through its transmembrane domain. TRAF3IP3-induced ER stress-mediated apoptosis and cytoprotective autophagy are dependent on STRN3, identified by IP-MS as a direct downstream interactor.\",\n      \"method\": \"IP-MS identification of STRN3 as binding partner, co-immunoprecipitation, transmembrane domain mutational analysis, ER stress pathway analysis (PERK/ATF4/CHOP), STRN3 knockdown rescue experiments, cell viability/apoptosis assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS interaction, co-IP, functional dependence on STRN3 and transmembrane domain, single lab\",\n      \"pmids\": [\"40068093\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRAF3IP3 (T3JAM) is a multi-compartment adapter protein that localizes to distinct organelles (Golgi, lysosome, mitochondria, ER) to regulate immune signaling: at the Golgi it recruits MEK to facilitate BRAF-MEK-ERK activation during T cell development; at the lysosome it recruits PP2Ac to dephosphorylate the mTORC1 component Raptor and restrain glycolysis in regulatory T cells; on mitochondria it bridges MAVS and TRAF3 to activate TBK1-IRF3-driven interferon production, while also interacting with TBK1 to promote its K48 ubiquitination via DTX4 and limit excess IFN-I in myeloid cells; it promotes autophagy via an ATG16L1-binding motif in B cells; it blocks mitophagy by promoting NEDD4 degradation in cardiomyocytes; and it recruits STRN3 to the ER lumen via its transmembrane domain to drive ER stress-mediated apoptosis in lung adenocarcinoma cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRAF3IP3 (T3JAM) is a multi-compartment adapter protein that couples organelle-specific scaffolding to immune signaling, T cell development, and cell-fate decisions [#1, #4]. It was first defined as a TRAF3-specific binding partner that recruits TRAF3 to a detergent-insoluble fraction and selectively drives JNK rather than NF-\\u03baB activation [#0]. In the secretory pathway TRAF3IP3 localizes to the Golgi/trans-Golgi network, where it recruits MEK and promotes its interaction with BRAF to enable TCR-stimulated ERK activation during thymocyte positive selection and NKT2 maturation; a constitutively active MEK transgene rescues the T cell development block in knockout mice [#1, #5]. At the lysosome it recruits the phosphatase catalytic subunit PP2Ac to engage the mTORC1 component Raptor, thereby restraining mTORC1-driven glycolysis and stabilizing regulatory T cells [#3]. In antiviral innate immunity TRAF3IP3 has dual, compartment-dependent roles: it accumulates on mitochondria upon viral infection to bridge TRAF3 to MAVS and license TBK1-IRF3-driven interferon production [#4], while also interacting with TRAF3 and TBK1 to direct DTX4-dependent K48-linked ubiquitination of TBK1 at K372, limiting excess type I interferon in myeloid cells [#6]. TRAF3IP3 additionally regulates autophagic pathways, promoting autophagy via an ATG16L1-binding motif to sustain marginal zone B cell survival [#2] and blocking mitophagy by promoting NEDD4 degradation in cardiomyocytes [#8]. Through its transmembrane domain it recruits STRN3 to the ER to trigger PERK/ATF4/CHOP-mediated ER stress and apoptosis in lung adenocarcinoma cells [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established TRAF3IP3 as a TRAF-selective adapter, answering whether it engages the TRAF family broadly or specifically and which downstream pathway it routes to.\",\n      \"evidence\": \"Co-IP across TRAF family members, subcellular fractionation, and JNK/NF-\\u03baB reporter assays in overexpression systems\",\n      \"pmids\": [\"14572659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous TRAF3 association not shown\", \"Physiological cell context and stimulus undefined\", \"Structural basis of TRAF3 specificity unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved a developmental function by placing TRAF3IP3 at the Golgi as the scaffold that couples MEK to BRAF for TCR-driven ERK signaling during thymocyte positive selection.\",\n      \"evidence\": \"Conditional knockout mice, subcellular localization, MEK-BRAF co-IP, and genetic rescue with constitutively active MEK\",\n      \"pmids\": [\"26195727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRAF3IP3 is targeted to the Golgi not defined\", \"Direct vs. indirect MEK binding interface unmapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified an autophagy-promoting role via an ATG16L1-binding motif, linking TRAF3IP3 to marginal zone B cell survival.\",\n      \"evidence\": \"Knockout mice, autophagy and apoptosis assays, and mutational analysis of the ATG16L1-binding motif\",\n      \"pmids\": [\"26011558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ATG16L1 binding via the motif not biochemically confirmed\", \"Subcellular site of this interaction undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a lysosomal, metabolism-restraining function: TRAF3IP3 recruits PP2Ac to dephosphorylate the mTORC1 component Raptor and limit glycolysis in Tregs.\",\n      \"evidence\": \"Treg-specific conditional knockout, lysosomal fractionation, PP2Ac-Raptor co-IP, and metabolic/mTORC1 activity assays\",\n      \"pmids\": [\"30115741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of lysosomal targeting unclear\", \"Whether Raptor is the direct PP2Ac dephosphorylation substrate not demonstrated enzymatically\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a positive antiviral role by showing mitochondrial TRAF3IP3 bridges TRAF3 to MAVS to drive TBK1-IRF3 interferon responses.\",\n      \"evidence\": \"Knockout mice, virus infection assays, TRAF3-MAVS co-IP, and mitochondrial localization linked to IFN output\",\n      \"pmids\": [\"31390091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for mitochondrial accumulation undefined\", \"Direct binding topology among TRAF3IP3/TRAF3/MAVS unmapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the Golgi-MEK-ERK axis to NKT2 cell maturation, generalizing the trans-Golgi scaffolding role beyond conventional thymocytes.\",\n      \"evidence\": \"T-cell-specific conditional knockout, trans-Golgi localization, MEK1 co-IP, and ERK phosphorylation/nuclear translocation assays\",\n      \"pmids\": [\"31076725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct MEK1 binding interface not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed an opposing, negative-feedback function in myeloid cells: TRAF3IP3 promotes DTX4-dependent K48 ubiquitination of TBK1 at K372 to restrain excess IFN-I.\",\n      \"evidence\": \"Myeloid-specific conditional knockout, TRAF3/TBK1 co-IP, ubiquitination site mapping, and DTX4 genetic epistasis\",\n      \"pmids\": [\"32366851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cell-type context switches TRAF3IP3 between pro- and anti-IFN roles unresolved\", \"Whether the same molecular pool performs both functions unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Characterized TRAF3IP3 as a restriction factor cleaved by enterovirus 3C protease and identified functional NLS/NES elements governing its antiviral activity.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, immunofluorescence, cleavage site mapping (87Q-88G), and NLS/NES functional analysis in Jurkat and RD cells\",\n      \"pmids\": [\"35814660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear function of TRAF3IP3 not mechanistically defined\", \"Relationship between nuclear shuttling and organelle-based roles unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed TRAF3IP3 blocks mitophagy by promoting NEDD4 degradation, worsening myocardial ischemia-reperfusion injury.\",\n      \"evidence\": \"Co-IP, cycloheximide chase, knockdown in H9C2 cells, and an in vivo I/R rat model\",\n      \"pmids\": [\"39240426\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TRAF3IP3 promotes NEDD4 turnover not defined\", \"Link from NEDD4 loss to mitophagy block not fully mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an ER-localized, pro-apoptotic function: TRAF3IP3 uses its transmembrane domain to recruit STRN3 and trigger PERK/ATF4/CHOP ER stress in lung adenocarcinoma.\",\n      \"evidence\": \"IP-MS, co-IP, transmembrane domain mutagenesis, STRN3 knockdown rescue, and apoptosis/viability assays\",\n      \"pmids\": [\"40068093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct STRN3 binding interface beyond TM dependence unmapped\", \"How ER targeting is coordinated with other organelle pools unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single adapter is partitioned among Golgi, lysosome, mitochondria, ER, and nucleus, and what governs its context-dependent switching between opposing functions (pro- vs. anti-interferon; autophagy vs. mitophagy).\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model defines distinct organelle-targeting determinants\", \"No single study compares multiple compartmental pools in one cell type\", \"Direct binding interfaces for most partners (MEK, MAVS, PP2Ac, STRN3) unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRAF3\", \"MEK1\", \"BRAF\", \"MAVS\", \"TBK1\", \"PP2Ac\", \"ATG16L1\", \"STRN3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}