{"gene":"TRAF3IP3","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":2003,"finding":"TRAF3IP3 (T3JAM) specifically interacts with TRAF3 (but not other TRAF family members) and synergistically activates JNK but not NF-κB; coexpression with TRAF3 recruits TRAF3 to the detergent-insoluble fraction, suggesting T3JAM functions as an adapter molecule regulating TRAF3-mediated JNK activation.","method":"Co-immunoprecipitation, subcellular fractionation, reporter assays (JNK and NF-κB activation)","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal interaction and functional assays in a single lab with multiple readouts","pmids":["14572659"],"is_preprint":false},{"year":2015,"finding":"TRAF3IP3 localizes to the Golgi and mediates TCR-stimulated ERK/MEK activation during thymocyte development by recruiting MEK to the Golgi, thereby facilitating MEK interaction with its activator BRAF; Traf3ip3 knockout causes impaired positive selection, rescued by constitutively active MEK transgene.","method":"Traf3ip3 knockout mice, genetic rescue with constitutively active MEK transgene, subcellular fractionation/localization, co-immunoprecipitation, ERK/MEK activation assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined phenotype, genetic epistasis rescue, and direct localization with mechanistic consequence","pmids":["26195727"],"is_preprint":false},{"year":2015,"finding":"TRAF3IP3 promotes autophagy via an ATG16L1-binding motif; loss of TRAF3IP3 in mice leads to impaired B cell development, loss of marginal zone B cells, diminished autophagy, and increased apoptosis in MZ B cells.","method":"Traf3ip3 knockout mice, autophagy assays, identification of ATG16L1-binding motif by mutagenesis/interaction studies","journal":"Clinical and experimental immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 — KO mouse with defined cellular phenotype plus identification of functional motif, single lab","pmids":["26011558"],"is_preprint":false},{"year":2018,"finding":"Lysosomal TRAF3IP3 restricts mTORC1 signaling in regulatory T cells by recruiting the PP2Ac catalytic subunit to the lysosome, facilitating PP2Ac interaction with the mTORC1 component Raptor; Treg-specific deletion of Traf3ip3 causes hyper-glycolytic metabolism and impaired Treg function via excessive mTORC1 activity.","method":"Treg-specific Traf3ip3 knockout mice, co-immunoprecipitation of PP2Ac with Raptor, lysosomal fractionation, mTORC1 activity assays, metabolic profiling","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO, co-IP of complex at lysosome, multiple orthogonal methods","pmids":["30115741"],"is_preprint":false},{"year":2019,"finding":"TRAF3IP3 accumulates on mitochondria upon virus infection and mediates recruitment of TRAF3 to MAVS (mitochondrial antiviral signaling protein), enabling TBK1-IRF3 activation and interferon production; Traf3ip3-deficient mice show severely compromised interferon induction and increased susceptibility to RNA virus infection.","method":"Traf3ip3 knockout mice, co-immunoprecipitation, mitochondrial localization assays, interferon reporter assays, viral challenge experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — KO mice with viral phenotype, co-IP showing TRAF3-MAVS bridging, multiple orthogonal methods","pmids":["31390091"],"is_preprint":false},{"year":2019,"finding":"TRAF3IP3 at the trans-Golgi network recruits MEK1 and facilitates ERK phosphorylation and nuclear translocation to regulate NKT2 cell maturation; T-cell-specific deletion of TRAF3IP3 reduces thymic NKT2 cells and impairs IL-4 production.","method":"T-cell-specific Traf3ip3 knockout mice, subcellular localization/fractionation, co-immunoprecipitation of MEK1 with TRAF3IP3 at trans-Golgi, ERK phosphorylation assays, flow cytometry","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with defined phenotype and direct localization with mechanistic consequence, single lab","pmids":["31076725"],"is_preprint":false},{"year":2020,"finding":"TRAF3IP3 suppresses cytosolic RNA-triggered type I interferon production by interacting with TRAF3 and TBK1 and promoting K48-linked (degradative) ubiquitination of TBK1 at K372 in a DTX4-dependent manner; myeloid-specific Traf3ip3 knockout mice show enhanced IFN-I production and resistance to RNA virus.","method":"Traf3ip3 knockout and myeloid-specific knockout mice, co-immunoprecipitation of endogenous TRAF3 and TBK1, ubiquitination assays with K48 linkage-specific analysis, site-directed mutagenesis (K372), DTX4 dependence assays, viral challenge","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — enzymatic ubiquitination assay with mutagenesis, KO mice, multiple orthogonal methods","pmids":["32366851"],"is_preprint":false},{"year":2022,"finding":"TRAF3IP3 interacts with EV71 3C protease; 3Cpro cleaves TRAF3IP3 at the 87Q-88G site, partially overcoming TRAF3IP3-mediated inhibition of EV71 replication; the nuclear export signal (NES) of TRAF3IP3 contributes to its antiviral function by altering 3Cpro localization.","method":"Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence, in vitro cleavage assays, identification of cleavage site by mutagenesis, viral replication assays in Jurkat and RD cells, NLS/NES mapping","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods including cleavage site mutagenesis and functional antiviral assays, single lab","pmids":["35814660"],"is_preprint":false},{"year":2024,"finding":"TRAF3IP3 blocks mitophagy and exacerbates myocardial ischemia-reperfusion injury by promoting degradation of the NEDD4 protein; TRAF3IP3 knockdown induces mitophagy and enhances mitochondrial function, reducing cardiomyocyte damage.","method":"Co-immunoprecipitation, CHX chase assay (protein stability), immunoblot, immunostaining, TRAF3IP3 knockdown in H9C2 cells and I/R rat model, mitophagy and ATP assays","journal":"Cardiovascular toxicology","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP and functional KD with multiple cellular readouts, single lab","pmids":["39240426"],"is_preprint":false},{"year":2025,"finding":"TRAF3IP3 induces ER stress-mediated apoptosis via the PERK/ATF4/CHOP pathway and triggers ER stress-induced cytoprotective autophagy in lung adenocarcinoma cells; IP-MS identified STRN3 as a direct downstream interactor, and TRAF3IP3 recruits STRN3 to the ER lumen via its transmembrane domain to regulate ER stress in an STRN3-dependent manner.","method":"IP-MS (immunoprecipitation-mass spectrometry), co-immunoprecipitation, transmembrane domain mutagenesis, ER stress pathway assays (PERK/ATF4/CHOP), apoptosis and autophagy assays in LUAD cells","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — IP-MS with functional validation and domain mutagenesis, single lab","pmids":["40068093"],"is_preprint":false}],"current_model":"TRAF3IP3 is a multifunctional adapter protein that operates at distinct subcellular compartments (Golgi, lysosomes, mitochondria, ER) to regulate immune signaling: it recruits MEK to the Golgi to facilitate BRAF-MEK-ERK activation during T cell development, recruits PP2Ac to the lysosome to suppress mTORC1-Raptor signaling in regulatory T cells, accumulates on mitochondria to bridge MAVS and TRAF3 for TBK1-IRF3-driven interferon production after RNA virus sensing, promotes degradative K48-ubiquitination of TBK1 at K372 via DTX4 to negatively regulate antiviral IFN-I responses, promotes autophagy via an ATG16L1-binding motif for B cell survival, recruits STRN3 to the ER to drive ER stress-mediated apoptosis, and blocks NEDD4-dependent mitophagy in cardiomyocytes."},"narrative":{"teleology":[{"year":2003,"claim":"Identification of TRAF3IP3 as a TRAF3-specific adapter that selectively activates JNK — but not NF-κB — established the gene as a signaling scaffold linking TRAF3 to MAP kinase pathways.","evidence":"Co-immunoprecipitation, subcellular fractionation, and reporter assays in transfected cells","pmids":["14572659"],"confidence":"Medium","gaps":["Interaction shown only with overexpression; endogenous co-IP not reported","Physiological cell type and stimulus context unknown","Mechanism by which TRAF3IP3 activates JNK not defined"]},{"year":2015,"claim":"Knockout studies revealed that TRAF3IP3 localizes to the Golgi and recruits MEK to BRAF, providing the mechanistic basis for TCR-stimulated ERK activation during thymocyte positive selection; a constitutively active MEK transgene rescued the selection defect, establishing genetic epistasis.","evidence":"Traf3ip3 knockout mice, genetic rescue with active MEK transgene, Golgi fractionation, co-immunoprecipitation","pmids":["26195727"],"confidence":"High","gaps":["How TRAF3IP3 itself is anchored at the Golgi was not resolved","Whether Golgi-localized TRAF3IP3 participates in non-ERK signaling at this compartment is unknown"]},{"year":2015,"claim":"Discovery of an ATG16L1-binding motif in TRAF3IP3 linked the adapter to autophagy and explained the loss of marginal zone B cells and increased apoptosis in knockout mice, broadening its role beyond classical signaling to cellular survival via autophagy.","evidence":"Traf3ip3 knockout mice, autophagy flux assays, ATG16L1-binding motif mutagenesis","pmids":["26011558"],"confidence":"Medium","gaps":["Direct structural basis for ATG16L1 interaction not determined","Whether autophagy function is B cell–specific or generalizable unclear"]},{"year":2018,"claim":"Demonstration that lysosomal TRAF3IP3 recruits PP2Ac to dephosphorylate the mTORC1 component Raptor explained how TRAF3IP3 restricts mTORC1 and glycolytic metabolism in regulatory T cells, revealing a second compartment-specific adapter function.","evidence":"Treg-specific Traf3ip3 conditional knockout, lysosomal fractionation, PP2Ac–Raptor co-IP, metabolic profiling","pmids":["30115741"],"confidence":"High","gaps":["Signal that directs TRAF3IP3 to lysosomes versus Golgi not identified","Whether PP2Ac recruitment operates in non-Treg lineages not tested"]},{"year":2019,"claim":"Two studies established TRAF3IP3's mitochondrial and Golgi roles in innate and adaptive immunity: upon RNA virus infection it accumulates on mitochondria to bridge TRAF3 to MAVS for TBK1-IRF3-IFN production, and at the trans-Golgi it recruits MEK1 for ERK-driven NKT2 cell maturation.","evidence":"Traf3ip3 KO and T-cell-specific conditional KO mice, viral challenge, co-IP of TRAF3–MAVS, mitochondrial localization, Golgi fractionation","pmids":["31390091","31076725"],"confidence":"High","gaps":["Stimulus-dependent trafficking signals from Golgi to mitochondria unresolved","Whether TRAF3IP3 simultaneously resides at both compartments or redistributes dynamically not determined"]},{"year":2020,"claim":"In myeloid cells, TRAF3IP3 promotes DTX4-dependent K48-ubiquitination of TBK1 at K372, revealing a negative-feedback mechanism for IFN-I that contrasts with its positive role in lymphoid antiviral signaling and demonstrating cell-type-specific duality.","evidence":"Myeloid-specific Traf3ip3 KO mice, K48-linkage-specific ubiquitination assays, K372 site-directed mutagenesis, viral challenge","pmids":["32366851"],"confidence":"High","gaps":["How TRAF3IP3 switches between promoting and inhibiting TBK1 signaling in different cell types is mechanistically undefined","Direct demonstration that DTX4 is the E3 ligase recruited by TRAF3IP3 (rather than correlative) not fully established"]},{"year":2022,"claim":"Identification of TRAF3IP3 as an EV71 3C protease substrate (cleaved at 87Q-88G) showed that a pathogen directly antagonizes TRAF3IP3's antiviral function, and mapped a nuclear export signal contributing to its activity.","evidence":"Yeast two-hybrid, in vitro cleavage assays with site-directed mutagenesis, viral replication assays in Jurkat and RD cells","pmids":["35814660"],"confidence":"Medium","gaps":["In vivo relevance of EV71-mediated cleavage not confirmed in animal models","Whether other picornaviruses also target TRAF3IP3 unknown"]},{"year":2024,"claim":"TRAF3IP3 was found to block NEDD4-dependent mitophagy and promote cardiomyocyte injury during ischemia-reperfusion, extending its functional scope to non-immune tissues and revealing a role in mitochondrial quality control.","evidence":"TRAF3IP3 knockdown in H9C2 cardiomyocytes and rat ischemia-reperfusion model, CHX chase for NEDD4 stability, mitophagy and ATP assays","pmids":["39240426"],"confidence":"Medium","gaps":["Mechanism by which TRAF3IP3 promotes NEDD4 degradation not characterized","Findings from a single lab in one cell line and one in vivo model; independent confirmation lacking"]},{"year":2025,"claim":"IP-MS identification of STRN3 as a direct TRAF3IP3 interactor at the ER, recruited via the TRAF3IP3 transmembrane domain, established a fourth compartment-specific function — driving PERK/ATF4/CHOP ER stress and apoptosis in lung adenocarcinoma cells.","evidence":"IP-MS, co-immunoprecipitation, transmembrane domain mutagenesis, ER stress pathway assays in LUAD cell lines","pmids":["40068093"],"confidence":"Medium","gaps":["STRN3-dependent ER stress mechanism awaits reconstitution with purified components","Relevance beyond lung adenocarcinoma cell lines not established"]},{"year":null,"claim":"The determinants that specify TRAF3IP3 localization to Golgi, lysosomes, mitochondria, or ER — and whether these reflect distinct pools or dynamic redistribution — remain undefined, as does a unifying structural model explaining how one adapter recruits such diverse effectors in a compartment-specific manner.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of TRAF3IP3 or its complexes","Sorting signals directing TRAF3IP3 to specific organelles not mapped","Cell-type-specific regulation of TRAF3IP3 expression and post-translational modifications not systematically characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,4,6]}],"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]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,3,4,5,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3,5,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9]}],"complexes":[],"partners":["TRAF3","MEK1","PPP2CA","MAVS","TBK1","ATG16L1","STRN3","DTX4"],"other_free_text":[]},"mechanistic_narrative":"TRAF3IP3 is a compartment-specific adapter protein that orchestrates immune signaling, autophagy, and stress responses by recruiting distinct effectors to the Golgi, lysosomes, mitochondria, and endoplasmic reticulum. At the Golgi, TRAF3IP3 recruits MEK to facilitate BRAF-MEK-ERK activation required for thymocyte positive selection and NKT2 cell maturation [PMID:26195727, PMID:31076725]; at lysosomes, it recruits PP2Ac to suppress mTORC1-Raptor signaling and maintain regulatory T cell function [PMID:30115741]; and at mitochondria, it bridges TRAF3 to MAVS to enable TBK1-IRF3-driven type I interferon production upon RNA virus sensing, while in myeloid cells it also promotes DTX4-dependent K48-ubiquitination of TBK1 at K372 to negatively regulate IFN-I, revealing cell-type-dependent dual roles in antiviral innate immunity [PMID:31390091, PMID:32366851]. TRAF3IP3 additionally promotes autophagy through an ATG16L1-binding motif essential for marginal zone B cell survival [PMID:26011558], recruits STRN3 to the ER to drive PERK/ATF4/CHOP-mediated ER stress and apoptosis [PMID:40068093], and inhibits NEDD4-dependent mitophagy in cardiomyocytes [PMID:39240426]."},"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":59,"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":46,"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":43,"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":13,"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":9,"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":"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":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":"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":6,"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":2,"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":2,"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":11277,"output_tokens":2727,"usd":0.037368},"stage2":{"model":"claude-opus-4-6","input_tokens":6042,"output_tokens":2932,"usd":0.155265},"total_usd":0.192633,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"TRAF3IP3 (T3JAM) specifically interacts with TRAF3 (but not other TRAF family members) and synergistically activates JNK but not NF-κB; coexpression with TRAF3 recruits TRAF3 to the detergent-insoluble fraction, suggesting T3JAM functions as an adapter molecule regulating TRAF3-mediated JNK activation.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, reporter assays (JNK and NF-κB activation)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction and functional assays in a single lab with multiple readouts\",\n      \"pmids\": [\"14572659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRAF3IP3 localizes to the Golgi and mediates TCR-stimulated ERK/MEK activation during thymocyte development by recruiting MEK to the Golgi, thereby facilitating MEK interaction with its activator BRAF; Traf3ip3 knockout causes impaired positive selection, rescued by constitutively active MEK transgene.\",\n      \"method\": \"Traf3ip3 knockout mice, genetic rescue with constitutively active MEK transgene, subcellular fractionation/localization, co-immunoprecipitation, ERK/MEK activation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined phenotype, genetic epistasis rescue, and direct localization with mechanistic consequence\",\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 mice leads to impaired B cell development, loss of marginal zone B cells, diminished autophagy, and increased apoptosis in MZ B cells.\",\n      \"method\": \"Traf3ip3 knockout mice, autophagy assays, identification of ATG16L1-binding motif by mutagenesis/interaction studies\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KO mouse with defined cellular phenotype plus identification of functional motif, 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 PP2Ac catalytic subunit to the lysosome, facilitating PP2Ac interaction with the mTORC1 component Raptor; Treg-specific deletion of Traf3ip3 causes hyper-glycolytic metabolism and impaired Treg function via excessive mTORC1 activity.\",\n      \"method\": \"Treg-specific Traf3ip3 knockout mice, co-immunoprecipitation of PP2Ac with Raptor, lysosomal fractionation, mTORC1 activity assays, metabolic profiling\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO, co-IP of complex at lysosome, multiple orthogonal methods\",\n      \"pmids\": [\"30115741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRAF3IP3 accumulates on mitochondria upon virus infection and mediates recruitment of TRAF3 to MAVS (mitochondrial antiviral signaling protein), enabling TBK1-IRF3 activation and interferon production; Traf3ip3-deficient mice show severely compromised interferon induction and increased susceptibility to RNA virus infection.\",\n      \"method\": \"Traf3ip3 knockout mice, co-immunoprecipitation, mitochondrial localization assays, interferon reporter assays, viral challenge experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice with viral phenotype, co-IP showing TRAF3-MAVS bridging, multiple orthogonal methods\",\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 to regulate NKT2 cell maturation; T-cell-specific deletion of TRAF3IP3 reduces thymic NKT2 cells and impairs IL-4 production.\",\n      \"method\": \"T-cell-specific Traf3ip3 knockout mice, subcellular localization/fractionation, co-immunoprecipitation of MEK1 with TRAF3IP3 at trans-Golgi, ERK phosphorylation assays, flow cytometry\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined phenotype and direct localization with mechanistic consequence, single lab\",\n      \"pmids\": [\"31076725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRAF3IP3 suppresses cytosolic RNA-triggered type I interferon production by interacting with TRAF3 and TBK1 and promoting K48-linked (degradative) ubiquitination of TBK1 at K372 in a DTX4-dependent manner; myeloid-specific Traf3ip3 knockout mice show enhanced IFN-I production and resistance to RNA virus.\",\n      \"method\": \"Traf3ip3 knockout and myeloid-specific knockout mice, co-immunoprecipitation of endogenous TRAF3 and TBK1, ubiquitination assays with K48 linkage-specific analysis, site-directed mutagenesis (K372), DTX4 dependence assays, viral challenge\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — enzymatic ubiquitination assay with mutagenesis, KO mice, multiple orthogonal methods\",\n      \"pmids\": [\"32366851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRAF3IP3 interacts with EV71 3C protease; 3Cpro cleaves TRAF3IP3 at the 87Q-88G site, partially overcoming TRAF3IP3-mediated inhibition of EV71 replication; the nuclear export signal (NES) of TRAF3IP3 contributes to its antiviral function by altering 3Cpro localization.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence, in vitro cleavage assays, identification of cleavage site by mutagenesis, viral replication assays in Jurkat and RD cells, NLS/NES mapping\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods including cleavage site mutagenesis and functional antiviral assays, single lab\",\n      \"pmids\": [\"35814660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRAF3IP3 blocks mitophagy and exacerbates myocardial ischemia-reperfusion injury by promoting degradation of the NEDD4 protein; TRAF3IP3 knockdown induces mitophagy and enhances mitochondrial function, reducing cardiomyocyte damage.\",\n      \"method\": \"Co-immunoprecipitation, CHX chase assay (protein stability), immunoblot, immunostaining, TRAF3IP3 knockdown in H9C2 cells and I/R rat model, mitophagy and ATP assays\",\n      \"journal\": \"Cardiovascular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP and functional KD with multiple cellular readouts, single lab\",\n      \"pmids\": [\"39240426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRAF3IP3 induces ER stress-mediated apoptosis via the PERK/ATF4/CHOP pathway and triggers ER stress-induced cytoprotective autophagy in lung adenocarcinoma cells; IP-MS identified STRN3 as a direct downstream interactor, and TRAF3IP3 recruits STRN3 to the ER lumen via its transmembrane domain to regulate ER stress in an STRN3-dependent manner.\",\n      \"method\": \"IP-MS (immunoprecipitation-mass spectrometry), co-immunoprecipitation, transmembrane domain mutagenesis, ER stress pathway assays (PERK/ATF4/CHOP), apoptosis and autophagy assays in LUAD cells\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — IP-MS with functional validation and domain mutagenesis, single lab\",\n      \"pmids\": [\"40068093\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRAF3IP3 is a multifunctional adapter protein that operates at distinct subcellular compartments (Golgi, lysosomes, mitochondria, ER) to regulate immune signaling: it recruits MEK to the Golgi to facilitate BRAF-MEK-ERK activation during T cell development, recruits PP2Ac to the lysosome to suppress mTORC1-Raptor signaling in regulatory T cells, accumulates on mitochondria to bridge MAVS and TRAF3 for TBK1-IRF3-driven interferon production after RNA virus sensing, promotes degradative K48-ubiquitination of TBK1 at K372 via DTX4 to negatively regulate antiviral IFN-I responses, promotes autophagy via an ATG16L1-binding motif for B cell survival, recruits STRN3 to the ER to drive ER stress-mediated apoptosis, and blocks NEDD4-dependent mitophagy in cardiomyocytes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRAF3IP3 is a compartment-specific adapter protein that orchestrates immune signaling, autophagy, and stress responses by recruiting distinct effectors to the Golgi, lysosomes, mitochondria, and endoplasmic reticulum. At the Golgi, TRAF3IP3 recruits MEK to facilitate BRAF-MEK-ERK activation required for thymocyte positive selection and NKT2 cell maturation [PMID:26195727, PMID:31076725]; at lysosomes, it recruits PP2Ac to suppress mTORC1-Raptor signaling and maintain regulatory T cell function [PMID:30115741]; and at mitochondria, it bridges TRAF3 to MAVS to enable TBK1-IRF3-driven type I interferon production upon RNA virus sensing, while in myeloid cells it also promotes DTX4-dependent K48-ubiquitination of TBK1 at K372 to negatively regulate IFN-I, revealing cell-type-dependent dual roles in antiviral innate immunity [PMID:31390091, PMID:32366851]. TRAF3IP3 additionally promotes autophagy through an ATG16L1-binding motif essential for marginal zone B cell survival [PMID:26011558], recruits STRN3 to the ER to drive PERK/ATF4/CHOP-mediated ER stress and apoptosis [PMID:40068093], and inhibits NEDD4-dependent mitophagy in cardiomyocytes [PMID:39240426].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of TRAF3IP3 as a TRAF3-specific adapter that selectively activates JNK — but not NF-κB — established the gene as a signaling scaffold linking TRAF3 to MAP kinase pathways.\",\n      \"evidence\": \"Co-immunoprecipitation, subcellular fractionation, and reporter assays in transfected cells\",\n      \"pmids\": [\"14572659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction shown only with overexpression; endogenous co-IP not reported\",\n        \"Physiological cell type and stimulus context unknown\",\n        \"Mechanism by which TRAF3IP3 activates JNK not defined\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Knockout studies revealed that TRAF3IP3 localizes to the Golgi and recruits MEK to BRAF, providing the mechanistic basis for TCR-stimulated ERK activation during thymocyte positive selection; a constitutively active MEK transgene rescued the selection defect, establishing genetic epistasis.\",\n      \"evidence\": \"Traf3ip3 knockout mice, genetic rescue with active MEK transgene, Golgi fractionation, co-immunoprecipitation\",\n      \"pmids\": [\"26195727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How TRAF3IP3 itself is anchored at the Golgi was not resolved\",\n        \"Whether Golgi-localized TRAF3IP3 participates in non-ERK signaling at this compartment is unknown\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery of an ATG16L1-binding motif in TRAF3IP3 linked the adapter to autophagy and explained the loss of marginal zone B cells and increased apoptosis in knockout mice, broadening its role beyond classical signaling to cellular survival via autophagy.\",\n      \"evidence\": \"Traf3ip3 knockout mice, autophagy flux assays, ATG16L1-binding motif mutagenesis\",\n      \"pmids\": [\"26011558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct structural basis for ATG16L1 interaction not determined\",\n        \"Whether autophagy function is B cell–specific or generalizable unclear\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstration that lysosomal TRAF3IP3 recruits PP2Ac to dephosphorylate the mTORC1 component Raptor explained how TRAF3IP3 restricts mTORC1 and glycolytic metabolism in regulatory T cells, revealing a second compartment-specific adapter function.\",\n      \"evidence\": \"Treg-specific Traf3ip3 conditional knockout, lysosomal fractionation, PP2Ac–Raptor co-IP, metabolic profiling\",\n      \"pmids\": [\"30115741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Signal that directs TRAF3IP3 to lysosomes versus Golgi not identified\",\n        \"Whether PP2Ac recruitment operates in non-Treg lineages not tested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two studies established TRAF3IP3's mitochondrial and Golgi roles in innate and adaptive immunity: upon RNA virus infection it accumulates on mitochondria to bridge TRAF3 to MAVS for TBK1-IRF3-IFN production, and at the trans-Golgi it recruits MEK1 for ERK-driven NKT2 cell maturation.\",\n      \"evidence\": \"Traf3ip3 KO and T-cell-specific conditional KO mice, viral challenge, co-IP of TRAF3–MAVS, mitochondrial localization, Golgi fractionation\",\n      \"pmids\": [\"31390091\", \"31076725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stimulus-dependent trafficking signals from Golgi to mitochondria unresolved\",\n        \"Whether TRAF3IP3 simultaneously resides at both compartments or redistributes dynamically not determined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"In myeloid cells, TRAF3IP3 promotes DTX4-dependent K48-ubiquitination of TBK1 at K372, revealing a negative-feedback mechanism for IFN-I that contrasts with its positive role in lymphoid antiviral signaling and demonstrating cell-type-specific duality.\",\n      \"evidence\": \"Myeloid-specific Traf3ip3 KO mice, K48-linkage-specific ubiquitination assays, K372 site-directed mutagenesis, viral challenge\",\n      \"pmids\": [\"32366851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How TRAF3IP3 switches between promoting and inhibiting TBK1 signaling in different cell types is mechanistically undefined\",\n        \"Direct demonstration that DTX4 is the E3 ligase recruited by TRAF3IP3 (rather than correlative) not fully established\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of TRAF3IP3 as an EV71 3C protease substrate (cleaved at 87Q-88G) showed that a pathogen directly antagonizes TRAF3IP3's antiviral function, and mapped a nuclear export signal contributing to its activity.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro cleavage assays with site-directed mutagenesis, viral replication assays in Jurkat and RD cells\",\n      \"pmids\": [\"35814660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo relevance of EV71-mediated cleavage not confirmed in animal models\",\n        \"Whether other picornaviruses also target TRAF3IP3 unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"TRAF3IP3 was found to block NEDD4-dependent mitophagy and promote cardiomyocyte injury during ischemia-reperfusion, extending its functional scope to non-immune tissues and revealing a role in mitochondrial quality control.\",\n      \"evidence\": \"TRAF3IP3 knockdown in H9C2 cardiomyocytes and rat ischemia-reperfusion model, CHX chase for NEDD4 stability, mitophagy and ATP assays\",\n      \"pmids\": [\"39240426\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which TRAF3IP3 promotes NEDD4 degradation not characterized\",\n        \"Findings from a single lab in one cell line and one in vivo model; independent confirmation lacking\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"IP-MS identification of STRN3 as a direct TRAF3IP3 interactor at the ER, recruited via the TRAF3IP3 transmembrane domain, established a fourth compartment-specific function — driving PERK/ATF4/CHOP ER stress and apoptosis in lung adenocarcinoma cells.\",\n      \"evidence\": \"IP-MS, co-immunoprecipitation, transmembrane domain mutagenesis, ER stress pathway assays in LUAD cell lines\",\n      \"pmids\": [\"40068093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"STRN3-dependent ER stress mechanism awaits reconstitution with purified components\",\n        \"Relevance beyond lung adenocarcinoma cell lines not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The determinants that specify TRAF3IP3 localization to Golgi, lysosomes, mitochondria, or ER — and whether these reflect distinct pools or dynamic redistribution — remain undefined, as does a unifying structural model explaining how one adapter recruits such diverse effectors in a compartment-specific manner.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of TRAF3IP3 or its complexes\",\n        \"Sorting signals directing TRAF3IP3 to specific organelles not mapped\",\n        \"Cell-type-specific regulation of TRAF3IP3 expression and post-translational modifications not systematically characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 4, 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    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 3, 4, 5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3, 5, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TRAF3\",\n      \"MEK1\",\n      \"PPP2CA\",\n      \"MAVS\",\n      \"TBK1\",\n      \"ATG16L1\",\n      \"STRN3\",\n      \"DTX4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}