{"gene":"TICAM1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2003,"finding":"TICAM-1 physically binds the TIR domain of TLR3 and activates the IFN-β promoter in response to poly(I):poly(C), establishing it as the adaptor mediating TLR3-dependent IFN-β production independently of MyD88 and TIRAP.","method":"Co-immunoprecipitation (physical binding), IFN-β promoter reporter assay, overexpression in human cells","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assay plus functional promoter readout; independently confirmed by multiple subsequent labs","pmids":["12539043"],"is_preprint":false},{"year":2003,"finding":"TICAM-2 physically bridges TLR4 and TICAM-1, allowing LPS-TLR4 signaling to activate IRF-3 and IFN-β through TICAM-1; TICAM-1 does not directly bind TLR4.","method":"Co-immunoprecipitation, IFN-β promoter reporter assay, NF-κB reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus functional reporter assays; replicated in multiple subsequent studies","pmids":["14519765"],"is_preprint":false},{"year":2010,"finding":"TRAF2 binds the PxQxS motif (aa 333–338) of TICAM-1's N-terminal region; TRAF6 binds a separate site; both TRAF2 and TRAF6 act as E3 ligases to induce K63-linked ubiquitination of TICAM-1, cooperatively driving IFN-β induction and IRF-3/NF-κB activation. Double mutation of both TRAF2/6 binding sites completely abrogated IFN-β induction.","method":"Yeast two-hybrid screening, alanine-substitution mutagenesis, Co-immunoprecipitation, IFN-β promoter reporter assay, ubiquitination assay, confocal microscopy","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis, in-cell ubiquitination assay, and functional reporters combined in single study with rigorous controls","pmids":["20047764"],"is_preprint":false},{"year":2013,"finding":"The N-terminal domain of TICAM-1 (residues 1–153) folds into eight antiparallel helices with structural similarity to the IFIT family; this domain suppresses TICAM-1-mediated IFN-β promoter and NF-κB reporter activity, consistent with an auto-inhibitory role.","method":"X-ray crystallography (2.22 Å SAD structure), NF-κB and IFN-β promoter reporter assays","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation by reporter assays in a single rigorous study","pmids":["24311583"],"is_preprint":false},{"year":2009,"finding":"BS69, normally a nuclear transcriptional repressor, binds oligomerized TICAM-1 in the cytoplasm and translocates from the nucleus to the cytoplasm upon dsRNA stimulation; BS69 promotes TICAM-1 signalosome (speckle) formation and is required for full NF-κB/IRF-3 activation and IFN-β induction downstream of TLR3.","method":"Yeast two-hybrid, Co-immunoprecipitation, confocal microscopy, knockdown (siRNA), IFN-β/NF-κB reporter assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional knockdown/overexpression, single lab, multiple orthogonal methods","pmids":["19795416"],"is_preprint":false},{"year":2016,"finding":"14-3-3-zeta is required for TLR3-dependent TICAM-1 multimerization (signalosome formation); knockdown of 14-3-3-zeta blocks TICAM-1 multimer formation and reduces type I IFN production, IRF-3 nuclear translocation, and IκB phosphorylation via the TLR3-TICAM-1 pathway.","method":"Knockdown (siRNA), TICAM-1 multimerization assay, IRF-3 nuclear translocation assay, IFN and cytokine measurement","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD with multiple cellular readouts, single lab","pmids":["27058640"],"is_preprint":false},{"year":2016,"finding":"Raftlin mediates LPS-induced TLR4 internalization into endosomes and is required for TICAM-1-dependent IFN-β production but not NF-κB activation in human monocyte-derived DCs and macrophages; upon LPS stimulation Raftlin translocates from cytoplasm to plasma membrane, co-localizes with TLR4, and transiently binds TLR4 and clathrin via its association with clathrin-adaptor protein-2.","method":"Knockdown (siRNA), Co-immunoprecipitation, confocal microscopy, IFN-β reporter assay, ELISA","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, imaging, functional KD), single lab","pmids":["27022195"],"is_preprint":false},{"year":2011,"finding":"TICAM-1 protein level is down-regulated during TLR3 activation by dsRNA or rhinovirus in a lysosome-dependent, proteasome/caspase-independent manner, dependent on TLR3 but not RIG-I/MDA5/PKR; this down-regulation terminates TLR3-mediated IFN production, constituting a receptor desensitization mechanism.","method":"Protein level analysis (Western blot), pharmacological inhibitors (lysosome, proteasome, caspase), siRNA knockdown, virus infection assay","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inhibitor panel plus genetic knockdown with multiple cell types, single lab","pmids":["22205631"],"is_preprint":false},{"year":2017,"finding":"NMR structural analysis showed that TICAM-2 interacts with TICAM-1 via an acidic amino acid motif (E87/D88/D89) on TICAM-2; endosomal localization of TICAM-2 (dependent on N-terminal myristoylation and residues D91/E92) is essential for TLR4-mediated type I IFN signaling from the endosome.","method":"NMR structural analysis, mutagenesis of acidic motifs, functional reporter assays for IFN-β induction","journal":"Biochemical Society transactions","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — NMR structure plus mutagenesis in single review/research synthesis; limited primary experimental detail in abstract","pmids":["28630139"],"is_preprint":false},{"year":2021,"finding":"TICAM-1 binds to IL-17R adaptor Act1, competitively inhibiting IL-17RA–Act1 interaction; TICAM-1 knockout enhances IL-17RA/Act1 complex formation and amplifies IL-17A-mediated NF-κB and MAPK activation, leading to increased inflammatory cytokine/chemokine expression; TICAM-1 thus functions as a negative regulator of IL-17A signaling.","method":"Co-immunoprecipitation, TICAM-1 knockout mice, NF-κB/MAPK signaling assays, in vivo models (DTH, EAE)","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating direct binding plus knockout mice with multiple functional readouts, single lab","pmids":["34819358"],"is_preprint":false},{"year":2006,"finding":"In TICAM-1-deficient mice, polyI:C-induced NK-mDC contact-dependent antitumor NK activation and IL-12 production are abolished, while IFN production is preserved; TICAM-1 is required in myeloid DCs for DC maturation and NK cell activation leading to tumor regression.","method":"TICAM-1 knockout mice, syngeneic tumor implant model (B16 melanoma), adoptive transfer, in vivo transwell analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular and tumor phenotype, epistasis using multiple KO strains, single lab","pmids":["17190817"],"is_preprint":false},{"year":2012,"finding":"TICAM-1 signaling in CD8α+ dendritic cells is required for cross-priming of tumor-specific CTLs in response to polyI:C plus soluble antigen; IRF-3/7 are essential but IPS-1 plays only a minor role; TICAM-1-deficient mice fail to retard tumor growth in this model.","method":"TICAM-1 and IPS-1 knockout mice, H2Kb-SL8 tetramer assay, OT-1 proliferation assay, syngeneic tumor model (EG7/C57BL/6)","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple KO strains and antigen-specific T-cell readouts, single lab","pmids":["22934250"],"is_preprint":false},{"year":2011,"finding":"TICAM-1 is the dominant adaptor for TLR3-mediated IFN-β induction and host protection against poliovirus infection; TICAM-1-deficient PVR-transgenic mice are markedly more susceptible to poliovirus than IPS-1-deficient mice, and CD8α+/CD11c+ splenic DCs and macrophages are the primary IFN sources relying on TICAM-1.","method":"TICAM-1 and IPS-1 knockout mice in PVR-transgenic background, serum and organ IFN measurement, ex vivo/in vitro cell analysis","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in relevant disease model with multiple cell-type readouts, single lab","pmids":["21998457"],"is_preprint":false},{"year":2018,"finding":"TICAM-1 expression mediates TLR3-dependent (but not STING-dependent) sorting of miR-21 into extracellular vesicles; ectopic TICAM-1 expression increases EV miR-21 without changing intracellular miR-21, whereas MAVS does not have this effect; siRNA knockdown of TICAM-1 reduces EV miR-21 after TLR3 stimulation.","method":"Ectopic overexpression, siRNA knockdown, EV isolation, miRNA quantification","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single approach (overexpression/KD plus EV miRNA measurement), no mechanistic detail of sorting mechanism","pmids":["29679565"],"is_preprint":false},{"year":2018,"finding":"TICAM-1 is dispensable for STING-mediated IFN-β, IL-6, and CCL5 induction and DC maturation (CD80, CD86, CD40 upregulation) in bone marrow-derived and splenic myeloid cells; TICAM-1 knockout does not impair STING ligand responses in these cell types.","method":"TICAM-1 knockout mice, myeloid cell stimulation assays, cytokine mRNA measurement, flow cytometry","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple functional readouts; finding is a well-defined negative result with clear cellular context","pmids":["29627569"],"is_preprint":false},{"year":2017,"finding":"In Apc Min/+ mice, TICAM-1 knockout leads to accelerated polyposis, shorter survival, and increased c-Myc mRNA and protein in polyps; a Lactobacillus strain producing dsRNA was detected in feces, suggesting TLR3/TICAM-1 signaling by microbiota-derived dsRNA suppresses c-Myc-driven polyposis.","method":"TICAM-1 knockout in Apc Min/+ background, immunofluorescence, RT-PCR, survival analysis","journal":"Journal of biomedical science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic KO with phenotypic readout, but mechanistic link to c-Myc suppression is correlative and from single lab","pmids":["29041928"],"is_preprint":false}],"current_model":"TICAM-1 (TRIF) is a TIR-domain-containing adaptor that directly binds TLR3 (and is recruited to TLR4 via TICAM-2) to activate IRF-3 and NF-κB, thereby inducing IFN-β and inflammatory cytokines; its N-terminal domain (structurally related to IFIT proteins) exerts auto-inhibitory regulation, while TRAF2/TRAF6 bind distinct N-terminal motifs and catalyze K63-ubiquitination of TICAM-1 to drive full signaling, 14-3-3-zeta promotes TICAM-1 multimerization into a signalosome, BS69 enhances signalosome activity, Raftlin facilitates TLR4 endocytosis required for TICAM-1-dependent (but not MyD88-dependent) IFN-β production, TICAM-1 protein levels are reduced by a lysosomal pathway to provide negative feedback, and beyond TLR signaling TICAM-1 also competitively inhibits IL-17RA–Act1 interaction to dampen IL-17A-driven inflammation."},"narrative":{"mechanistic_narrative":"TICAM-1 (TRIF) is the TIR-domain adaptor that couples endosomal Toll-like receptor sensing of double-stranded RNA and LPS to type I interferon and inflammatory transcription, thereby orchestrating antiviral and antitumor innate immunity [PMID:12539043, PMID:14519765]. It is recruited to TLR3 by direct TIR-TIR interaction, while TLR4 signaling reaches TICAM-1 indirectly through the bridging adaptor TICAM-2 (TRAM), whose endosomal localization is essential for TLR4-driven IFN-β [PMID:14519765, PMID:28630139]. Signaling is gated at several levels: the N-terminal domain (residues 1–153) folds into an eight-helix, IFIT-like fold that auto-inhibits IFN-β and NF-κB output [PMID:24311583], and full activation requires TRAF2 and TRAF6 binding to distinct N-terminal motifs to catalyze K63-linked ubiquitination of TICAM-1, driving IRF-3 and NF-κB activation [PMID:20047764]. Productive signaling proceeds through assembly of a cytoplasmic TICAM-1 signalosome, which depends on 14-3-3-zeta for multimerization and is enhanced by the relocalized nuclear repressor BS69 [PMID:19795416, PMID:27058640]; for TLR4, Raftlin-dependent receptor endocytosis is specifically required for the TICAM-1 branch of IFN-β production [PMID:27022195]. The pathway is terminated by lysosome-dependent degradation of TICAM-1 that desensitizes TLR3 [PMID:22205631]. Genetically, TICAM-1 is required in dendritic cells for poly(I:C)-driven NK-cell activation, CD8α+ DC cross-priming of antitumor CTLs, and host defense against poliovirus [PMID:17190817, PMID:22934250, PMID:21998457]. Beyond TLR signaling, TICAM-1 also acts as a negative regulator of IL-17A responses by binding Act1 and competing with the IL-17RA–Act1 interaction [PMID:34819358].","teleology":[{"year":2003,"claim":"Established that a TIR adaptor distinct from MyD88 links TLR3 to interferon induction, defining the molecular basis of MyD88-independent antiviral signaling.","evidence":"Co-IP and IFN-β promoter reporter assays with poly(I:C) in human cells","pmids":["12539043"],"confidence":"High","gaps":["Does not resolve the downstream kinases or signalosome assembly","Overexpression system may not reflect endogenous stoichiometry"]},{"year":2003,"claim":"Explained how LPS-TLR4 reaches the same adaptor without direct binding, identifying TICAM-2 as the bridging adaptor that channels TLR4 into TICAM-1-dependent IFN-β.","evidence":"Co-IP plus IFN-β and NF-κB reporter assays","pmids":["14519765"],"confidence":"High","gaps":["Structural basis of the TICAM-2/TICAM-1 interface not resolved here","Subcellular compartment of the bridge unaddressed"]},{"year":2006,"claim":"Demonstrated that TICAM-1 is physiologically required in myeloid DCs for contact-dependent NK activation and antitumor responses, moving the adaptor from cytokine induction to cellular immunity.","evidence":"TICAM-1 knockout mice in B16 melanoma model with adoptive transfer and transwell analysis","pmids":["17190817"],"confidence":"Medium","gaps":["DC-NK contact signal molecularly undefined","Single tumor model"]},{"year":2010,"claim":"Identified the ubiquitin-dependent activation step, showing TRAF2 and TRAF6 bind distinct N-terminal motifs and K63-ubiquitinate TICAM-1 to drive IRF-3/NF-κB output.","evidence":"Yeast two-hybrid, alanine-scan mutagenesis, in-cell ubiquitination and IFN-β reporter assays","pmids":["20047764"],"confidence":"High","gaps":["DUBs that reverse the modification unknown","Chain topology assignment relies on in-cell assays"]},{"year":2011,"claim":"Revealed that TICAM-1 signaling is self-limiting via lysosomal degradation, establishing a receptor desensitization mechanism for TLR3.","evidence":"Western blot of protein levels with lysosome/proteasome/caspase inhibitors and siRNA during dsRNA or rhinovirus stimulation","pmids":["22205631"],"confidence":"Medium","gaps":["Trafficking machinery delivering TICAM-1 to lysosomes unidentified","No degradation-resistant mutant tested"]},{"year":2011,"claim":"Showed TICAM-1 is the dominant adaptor for antiviral protection in vivo, with TLR3-TICAM-1 outweighing the RIG-I/IPS-1 axis in poliovirus defense.","evidence":"TICAM-1 vs IPS-1 knockout in PVR-transgenic mice with IFN measurement","pmids":["21998457"],"confidence":"Medium","gaps":["Relative contribution may be virus-specific","IFN source cells inferred from ex vivo analysis"]},{"year":2012,"claim":"Connected TICAM-1 to adaptive immunity by showing it is required in CD8α+ DCs for poly(I:C)-driven cross-priming of antigen-specific CTLs.","evidence":"TICAM-1 and IPS-1 knockout mice with tetramer and OT-1 proliferation assays in EG7 tumor model","pmids":["22934250"],"confidence":"Medium","gaps":["Mechanism linking adaptor signaling to cross-presentation machinery undefined","Single antigen model"]},{"year":2009,"claim":"Identified BS69 as a cytoplasmic cofactor that promotes TICAM-1 signalosome (speckle) formation, beginning to explain how the adaptor oligomerizes for full activation.","evidence":"Yeast two-hybrid, Co-IP, confocal imaging, and siRNA knockdown with reporter assays","pmids":["19795416"],"confidence":"Medium","gaps":["Mechanism of nuclear-to-cytoplasmic relocation unclear","Single lab"]},{"year":2013,"claim":"Provided the structural basis for intramolecular regulation, showing the N-terminal IFIT-like helical domain auto-inhibits TICAM-1 signaling.","evidence":"2.22 Å X-ray crystal structure of residues 1–153 with IFN-β/NF-κB reporter validation","pmids":["24311583"],"confidence":"High","gaps":["Structure of full-length or signalosome state not solved","Trigger that relieves auto-inhibition unknown"]},{"year":2016,"claim":"Established 14-3-3-zeta as a required factor for TICAM-1 multimerization, mechanistically linking signalosome assembly to downstream IRF-3/IκB activation.","evidence":"siRNA knockdown with multimerization, IRF-3 translocation, and cytokine readouts","pmids":["27058640"],"confidence":"Medium","gaps":["Direct vs indirect binding to TICAM-1 not resolved","Single lab"]},{"year":2016,"claim":"Showed that TLR4 endocytosis via Raftlin is selectively required for the TICAM-1/IFN-β branch but not NF-κB, explaining spatial control of adaptor usage.","evidence":"siRNA, Co-IP with TLR4/clathrin/AP-2, confocal imaging, and IFN-β readouts in human DCs/macrophages","pmids":["27022195"],"confidence":"Medium","gaps":["Direct TICAM-1 engagement at endosome not shown","Human myeloid cells only"]},{"year":2017,"claim":"Defined the molecular interface and compartment requirement for TLR4 signaling, mapping the TICAM-2 acidic motif that engages TICAM-1 and the endosomal localization needed for IFN.","evidence":"NMR structural analysis and mutagenesis of acidic motifs with IFN-β reporters","pmids":["28630139"],"confidence":"Medium","gaps":["Limited primary experimental detail","Reciprocal TICAM-1 interface residues not mapped here"]},{"year":2018,"claim":"Delimited the pathway specificity of TICAM-1 by showing it is dispensable for STING-driven IFN and DC maturation, distinguishing TLR3 from cytosolic DNA sensing.","evidence":"TICAM-1 knockout myeloid cells with cytokine mRNA and flow cytometry","pmids":["29627569"],"confidence":"Medium","gaps":["Negative result; does not exclude minor roles in other cell types"]},{"year":2018,"claim":"Proposed a non-canonical role in directing TLR3-dependent sorting of miR-21 into extracellular vesicles.","evidence":"Ectopic overexpression and siRNA knockdown with EV miRNA quantification","pmids":["29679565"],"confidence":"Low","gaps":["Single approach with no sorting mechanism defined","Not independently confirmed"]},{"year":2021,"claim":"Extended TICAM-1 function beyond TLR signaling, showing it negatively regulates IL-17A responses by competing with the IL-17RA–Act1 interaction.","evidence":"Co-IP, TICAM-1 knockout mice, NF-κB/MAPK assays, and in vivo DTH/EAE models","pmids":["34819358"],"confidence":"Medium","gaps":["Structural basis of TICAM-1/Act1 competition undefined","Single lab"]},{"year":2017,"claim":"Linked TICAM-1 to intestinal tumor suppression in a microbiota-dependent manner, correlating its loss with accelerated, c-Myc-driven polyposis.","evidence":"TICAM-1 knockout in Apc Min/+ mice with immunofluorescence, RT-PCR, and survival analysis","pmids":["29041928"],"confidence":"Low","gaps":["c-Myc link is correlative","dsRNA-producing bacterium not causally tested"]},{"year":null,"claim":"How auto-inhibition is relieved and the ubiquitinated, 14-3-3/BS69-assisted signalosome assembles into an active full-length structure remains structurally unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No full-length or oligomeric structure","Order and interdependence of ubiquitination, multimerization, and auto-inhibition relief unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,5]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[6,8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,10,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,9]}],"complexes":["TICAM-1 signalosome"],"partners":["TLR3","TICAM2","TRAF2","TRAF6","BS69","YWHAZ","TRAF3IP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IUC6","full_name":"TIR domain-containing adapter molecule 1","aliases":["Proline-rich, vinculin and TIR domain-containing protein B","Putative NF-kappa-B-activating protein 502H","Toll-interleukin-1 receptor domain-containing adapter protein inducing interferon beta","MyD88-3","TIR domain-containing adapter protein inducing IFN-beta"],"length_aa":712,"mass_kda":76.4,"function":"Involved in innate immunity against invading pathogens. Adapter used by TLR3, TLR4 (through TICAM2) and TLR5 to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis (PubMed:12471095, PubMed:12539043, PubMed:14739303, PubMed:28747347, PubMed:35215908). Ligand binding to these receptors results in TRIF recruitment through its TIR domain (PubMed:12471095, PubMed:12539043, PubMed:14739303). Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively (PubMed:12471095, PubMed:12539043, PubMed:14739303). Phosphorylation by TBK1 on the pLxIS motif leads to recruitment and subsequent activation of the transcription factor IRF3 to induce expression of type I interferon and exert a potent immunity against invading pathogens (PubMed:25636800). Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of pro-inflammatory cytokines (By similarity)","subcellular_location":"Cytoplasmic vesicle, autophagosome; Cytoplasm, cytosol; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q8IUC6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TICAM1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TICAM1","total_profiled":1310},"omim":[{"mim_id":"619990","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 7; TMED7","url":"https://www.omim.org/entry/619990"},{"mim_id":"619138","title":"NEDD4-BINDING PROTEIN 1; N4BP1","url":"https://www.omim.org/entry/619138"},{"mim_id":"618755","title":"SHORT TRANSMEMBRANE MITOCHONDRIAL PROTEIN 1; STMP1","url":"https://www.omim.org/entry/618755"},{"mim_id":"618638","title":"HECT DOMAIN E3 UBIQUITIN PROTEIN LIGASE 3; HECTD3","url":"https://www.omim.org/entry/618638"},{"mim_id":"618080","title":"WD REPEAT-AND FYVE DOMAIN-CONTAINING PROTEIN 1; WDFY1","url":"https://www.omim.org/entry/618080"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"},{"location":"Nucleoli","reliability":"Uncertain"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":44.2}],"url":"https://www.proteinatlas.org/search/TICAM1"},"hgnc":{"alias_symbol":["TRIF","TICAM-1","MGC35334","PRVTIRB"],"prev_symbol":[]},"alphafold":{"accession":"Q8IUC6","domains":[{"cath_id":"1.25.40.780","chopping":"9-83_91-145","consensus_level":"high","plddt":88.2495,"start":9,"end":145},{"cath_id":"3.40.50.10140","chopping":"396-529","consensus_level":"high","plddt":82.0604,"start":396,"end":529}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IUC6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IUC6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IUC6-F1-predicted_aligned_error_v6.png","plddt_mean":62.78},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TICAM1","jax_strain_url":"https://www.jax.org/strain/search?query=TICAM1"},"sequence":{"accession":"Q8IUC6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IUC6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IUC6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IUC6"}},"corpus_meta":[{"pmid":"12539043","id":"PMC_12539043","title":"TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction.","date":"2003","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12539043","citation_count":928,"is_preprint":false},{"pmid":"14519765","id":"PMC_14519765","title":"TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14519765","citation_count":303,"is_preprint":false},{"pmid":"17190817","id":"PMC_17190817","title":"Antitumor NK activation induced by the Toll-like receptor 3-TICAM-1 (TRIF) pathway in myeloid dendritic cells.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17190817","citation_count":149,"is_preprint":false},{"pmid":"21998457","id":"PMC_21998457","title":"The TLR3/TICAM-1 pathway is mandatory for innate immune responses to poliovirus infection.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21998457","citation_count":79,"is_preprint":false},{"pmid":"20047764","id":"PMC_20047764","title":"Direct binding of TRAF2 and TRAF6 to TICAM-1/TRIF adaptor participates in activation of the Toll-like receptor 3/4 pathway.","date":"2010","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20047764","citation_count":71,"is_preprint":false},{"pmid":"19120474","id":"PMC_19120474","title":"Functional evolution of the TICAM-1 pathway for extrinsic RNA sensing.","date":"2009","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/19120474","citation_count":55,"is_preprint":false},{"pmid":"22934250","id":"PMC_22934250","title":"Cross-priming for antitumor CTL induced by soluble Ag + polyI:C depends on the TICAM-1 pathway in mouse CD11c(+)/CD8α(+) dendritic cells.","date":"2012","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/22934250","citation_count":55,"is_preprint":false},{"pmid":"27022195","id":"PMC_27022195","title":"Raftlin Controls Lipopolysaccharide-Induced TLR4 Internalization and TICAM-1 Signaling in a Cell Type-Specific Manner.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27022195","citation_count":52,"is_preprint":false},{"pmid":"15618008","id":"PMC_15618008","title":"TICAM-1 and TICAM-2: toll-like receptor adapters that participate in induction of type 1 interferons.","date":"2005","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15618008","citation_count":46,"is_preprint":false},{"pmid":"23162759","id":"PMC_23162759","title":"TLR3/TICAM-1 signaling in tumor cell RIP3-dependent necroptosis.","date":"2012","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/23162759","citation_count":45,"is_preprint":false},{"pmid":"28630139","id":"PMC_28630139","title":"Functional interfaces between TICAM-2/TRAM and TICAM-1/TRIF in TLR4 signaling.","date":"2017","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/28630139","citation_count":39,"is_preprint":false},{"pmid":"27834952","id":"PMC_27834952","title":"Double-stranded RNA promotes CTL-independent tumor cytolysis mediated by CD11b+Ly6G+ intratumor myeloid cells through the TICAM-1 signaling pathway.","date":"2016","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/27834952","citation_count":30,"is_preprint":false},{"pmid":"30405210","id":"PMC_30405210","title":"Effects of CRISPR/Cas9 dosage on TICAM1 and RBL gene mutation rate, embryonic development, hatchability and fry survival in channel catfish.","date":"2018","source":"Scientific 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Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39536991","citation_count":5,"is_preprint":false},{"pmid":"30716814","id":"PMC_30716814","title":"[Treg influences the pathogenesis of allergic rhinitis through TICAM-1 pathway].","date":"2018","source":"Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery","url":"https://pubmed.ncbi.nlm.nih.gov/30716814","citation_count":4,"is_preprint":false},{"pmid":"23832204","id":"PMC_23832204","title":"Crystallization and X-ray diffraction analysis of the N-terminal domain of the Toll-like receptor signalling adaptor protein TRIF/TICAM-1.","date":"2013","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/23832204","citation_count":4,"is_preprint":false},{"pmid":"38864429","id":"PMC_38864429","title":"Association between polymorphisms in TLR3, TICAM1 and IFNA1 genes and covid-19 severity in Southern Brazil.","date":"2024","source":"Expert review of molecular diagnostics","url":"https://pubmed.ncbi.nlm.nih.gov/38864429","citation_count":3,"is_preprint":false},{"pmid":"32243044","id":"PMC_32243044","title":"Correlation between TICAM1 gene polymorphisms and community-acquired pneumonia in children.","date":"2020","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/32243044","citation_count":2,"is_preprint":false},{"pmid":"40532577","id":"PMC_40532577","title":"Cilostazol attenuates vascular inflammation via the regulation of TICAM1/IRF3 signaling pathway.","date":"2025","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/40532577","citation_count":1,"is_preprint":false},{"pmid":"36951033","id":"PMC_36951033","title":"Can TRIF/TICAM-1 Dependent Pathway be Target Pathway in Lumbar Intervertebral Disc Degeneration?","date":"2023","source":"Turkish neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/36951033","citation_count":1,"is_preprint":false},{"pmid":"37668025","id":"PMC_37668025","title":"[Association of gene polymorphisms of MyD88 and TICAM1 and their interactions with community-acquired pneumonia in children].","date":"2023","source":"Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/37668025","citation_count":0,"is_preprint":false},{"pmid":"41633289","id":"PMC_41633289","title":"TICAM1 inhibits angiogenesis and accelerates inflammation in the healing of diabetic wounds via the NF-κB pathway.","date":"2026","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/41633289","citation_count":0,"is_preprint":false},{"pmid":"41378100","id":"PMC_41378100","title":"Identification of PGRMC1 as a regulator of the TLR3-TICAM1-IFNβ1 signaling axis in RAW264.7 macrophages.","date":"2025","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/41378100","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.05.636626","title":"Sex-dependent effects of intestinal epithelial TLR4 deletion induced before activity-based anorexia","date":"2025-02-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.05.636626","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.03.600853","title":"Innate immune system signaling and CD11b  <sup>+</sup>  CD11c  <sup>+</sup>  CD103  <sup>+</sup>  cell migration to the brain underlie changes in mouse behavior after microbial colonization","date":"2024-07-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.03.600853","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21557,"output_tokens":4173,"usd":0.063633,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11945,"output_tokens":4579,"usd":0.0871,"stage2_stop_reason":"end_turn"},"total_usd":0.150733,"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\": \"TICAM-1 physically binds the TIR domain of TLR3 and activates the IFN-β promoter in response to poly(I):poly(C), establishing it as the adaptor mediating TLR3-dependent IFN-β production independently of MyD88 and TIRAP.\",\n      \"method\": \"Co-immunoprecipitation (physical binding), IFN-β promoter reporter assay, overexpression in human cells\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assay plus functional promoter readout; independently confirmed by multiple subsequent labs\",\n      \"pmids\": [\"12539043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TICAM-2 physically bridges TLR4 and TICAM-1, allowing LPS-TLR4 signaling to activate IRF-3 and IFN-β through TICAM-1; TICAM-1 does not directly bind TLR4.\",\n      \"method\": \"Co-immunoprecipitation, IFN-β promoter reporter assay, NF-κB reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus functional reporter assays; replicated in multiple subsequent studies\",\n      \"pmids\": [\"14519765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRAF2 binds the PxQxS motif (aa 333–338) of TICAM-1's N-terminal region; TRAF6 binds a separate site; both TRAF2 and TRAF6 act as E3 ligases to induce K63-linked ubiquitination of TICAM-1, cooperatively driving IFN-β induction and IRF-3/NF-κB activation. Double mutation of both TRAF2/6 binding sites completely abrogated IFN-β induction.\",\n      \"method\": \"Yeast two-hybrid screening, alanine-substitution mutagenesis, Co-immunoprecipitation, IFN-β promoter reporter assay, ubiquitination assay, confocal microscopy\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis, in-cell ubiquitination assay, and functional reporters combined in single study with rigorous controls\",\n      \"pmids\": [\"20047764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The N-terminal domain of TICAM-1 (residues 1–153) folds into eight antiparallel helices with structural similarity to the IFIT family; this domain suppresses TICAM-1-mediated IFN-β promoter and NF-κB reporter activity, consistent with an auto-inhibitory role.\",\n      \"method\": \"X-ray crystallography (2.22 Å SAD structure), NF-κB and IFN-β promoter reporter assays\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation by reporter assays in a single rigorous study\",\n      \"pmids\": [\"24311583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BS69, normally a nuclear transcriptional repressor, binds oligomerized TICAM-1 in the cytoplasm and translocates from the nucleus to the cytoplasm upon dsRNA stimulation; BS69 promotes TICAM-1 signalosome (speckle) formation and is required for full NF-κB/IRF-3 activation and IFN-β induction downstream of TLR3.\",\n      \"method\": \"Yeast two-hybrid, Co-immunoprecipitation, confocal microscopy, knockdown (siRNA), IFN-β/NF-κB reporter assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional knockdown/overexpression, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19795416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"14-3-3-zeta is required for TLR3-dependent TICAM-1 multimerization (signalosome formation); knockdown of 14-3-3-zeta blocks TICAM-1 multimer formation and reduces type I IFN production, IRF-3 nuclear translocation, and IκB phosphorylation via the TLR3-TICAM-1 pathway.\",\n      \"method\": \"Knockdown (siRNA), TICAM-1 multimerization assay, IRF-3 nuclear translocation assay, IFN and cytokine measurement\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD with multiple cellular readouts, single lab\",\n      \"pmids\": [\"27058640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Raftlin mediates LPS-induced TLR4 internalization into endosomes and is required for TICAM-1-dependent IFN-β production but not NF-κB activation in human monocyte-derived DCs and macrophages; upon LPS stimulation Raftlin translocates from cytoplasm to plasma membrane, co-localizes with TLR4, and transiently binds TLR4 and clathrin via its association with clathrin-adaptor protein-2.\",\n      \"method\": \"Knockdown (siRNA), Co-immunoprecipitation, confocal microscopy, IFN-β reporter assay, ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, imaging, functional KD), single lab\",\n      \"pmids\": [\"27022195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TICAM-1 protein level is down-regulated during TLR3 activation by dsRNA or rhinovirus in a lysosome-dependent, proteasome/caspase-independent manner, dependent on TLR3 but not RIG-I/MDA5/PKR; this down-regulation terminates TLR3-mediated IFN production, constituting a receptor desensitization mechanism.\",\n      \"method\": \"Protein level analysis (Western blot), pharmacological inhibitors (lysosome, proteasome, caspase), siRNA knockdown, virus infection assay\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inhibitor panel plus genetic knockdown with multiple cell types, single lab\",\n      \"pmids\": [\"22205631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NMR structural analysis showed that TICAM-2 interacts with TICAM-1 via an acidic amino acid motif (E87/D88/D89) on TICAM-2; endosomal localization of TICAM-2 (dependent on N-terminal myristoylation and residues D91/E92) is essential for TLR4-mediated type I IFN signaling from the endosome.\",\n      \"method\": \"NMR structural analysis, mutagenesis of acidic motifs, functional reporter assays for IFN-β induction\",\n      \"journal\": \"Biochemical Society transactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — NMR structure plus mutagenesis in single review/research synthesis; limited primary experimental detail in abstract\",\n      \"pmids\": [\"28630139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TICAM-1 binds to IL-17R adaptor Act1, competitively inhibiting IL-17RA–Act1 interaction; TICAM-1 knockout enhances IL-17RA/Act1 complex formation and amplifies IL-17A-mediated NF-κB and MAPK activation, leading to increased inflammatory cytokine/chemokine expression; TICAM-1 thus functions as a negative regulator of IL-17A signaling.\",\n      \"method\": \"Co-immunoprecipitation, TICAM-1 knockout mice, NF-κB/MAPK signaling assays, in vivo models (DTH, EAE)\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating direct binding plus knockout mice with multiple functional readouts, single lab\",\n      \"pmids\": [\"34819358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In TICAM-1-deficient mice, polyI:C-induced NK-mDC contact-dependent antitumor NK activation and IL-12 production are abolished, while IFN production is preserved; TICAM-1 is required in myeloid DCs for DC maturation and NK cell activation leading to tumor regression.\",\n      \"method\": \"TICAM-1 knockout mice, syngeneic tumor implant model (B16 melanoma), adoptive transfer, in vivo transwell analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular and tumor phenotype, epistasis using multiple KO strains, single lab\",\n      \"pmids\": [\"17190817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TICAM-1 signaling in CD8α+ dendritic cells is required for cross-priming of tumor-specific CTLs in response to polyI:C plus soluble antigen; IRF-3/7 are essential but IPS-1 plays only a minor role; TICAM-1-deficient mice fail to retard tumor growth in this model.\",\n      \"method\": \"TICAM-1 and IPS-1 knockout mice, H2Kb-SL8 tetramer assay, OT-1 proliferation assay, syngeneic tumor model (EG7/C57BL/6)\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple KO strains and antigen-specific T-cell readouts, single lab\",\n      \"pmids\": [\"22934250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TICAM-1 is the dominant adaptor for TLR3-mediated IFN-β induction and host protection against poliovirus infection; TICAM-1-deficient PVR-transgenic mice are markedly more susceptible to poliovirus than IPS-1-deficient mice, and CD8α+/CD11c+ splenic DCs and macrophages are the primary IFN sources relying on TICAM-1.\",\n      \"method\": \"TICAM-1 and IPS-1 knockout mice in PVR-transgenic background, serum and organ IFN measurement, ex vivo/in vitro cell analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in relevant disease model with multiple cell-type readouts, single lab\",\n      \"pmids\": [\"21998457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TICAM-1 expression mediates TLR3-dependent (but not STING-dependent) sorting of miR-21 into extracellular vesicles; ectopic TICAM-1 expression increases EV miR-21 without changing intracellular miR-21, whereas MAVS does not have this effect; siRNA knockdown of TICAM-1 reduces EV miR-21 after TLR3 stimulation.\",\n      \"method\": \"Ectopic overexpression, siRNA knockdown, EV isolation, miRNA quantification\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single approach (overexpression/KD plus EV miRNA measurement), no mechanistic detail of sorting mechanism\",\n      \"pmids\": [\"29679565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TICAM-1 is dispensable for STING-mediated IFN-β, IL-6, and CCL5 induction and DC maturation (CD80, CD86, CD40 upregulation) in bone marrow-derived and splenic myeloid cells; TICAM-1 knockout does not impair STING ligand responses in these cell types.\",\n      \"method\": \"TICAM-1 knockout mice, myeloid cell stimulation assays, cytokine mRNA measurement, flow cytometry\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple functional readouts; finding is a well-defined negative result with clear cellular context\",\n      \"pmids\": [\"29627569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Apc Min/+ mice, TICAM-1 knockout leads to accelerated polyposis, shorter survival, and increased c-Myc mRNA and protein in polyps; a Lactobacillus strain producing dsRNA was detected in feces, suggesting TLR3/TICAM-1 signaling by microbiota-derived dsRNA suppresses c-Myc-driven polyposis.\",\n      \"method\": \"TICAM-1 knockout in Apc Min/+ background, immunofluorescence, RT-PCR, survival analysis\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic KO with phenotypic readout, but mechanistic link to c-Myc suppression is correlative and from single lab\",\n      \"pmids\": [\"29041928\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TICAM-1 (TRIF) is a TIR-domain-containing adaptor that directly binds TLR3 (and is recruited to TLR4 via TICAM-2) to activate IRF-3 and NF-κB, thereby inducing IFN-β and inflammatory cytokines; its N-terminal domain (structurally related to IFIT proteins) exerts auto-inhibitory regulation, while TRAF2/TRAF6 bind distinct N-terminal motifs and catalyze K63-ubiquitination of TICAM-1 to drive full signaling, 14-3-3-zeta promotes TICAM-1 multimerization into a signalosome, BS69 enhances signalosome activity, Raftlin facilitates TLR4 endocytosis required for TICAM-1-dependent (but not MyD88-dependent) IFN-β production, TICAM-1 protein levels are reduced by a lysosomal pathway to provide negative feedback, and beyond TLR signaling TICAM-1 also competitively inhibits IL-17RA–Act1 interaction to dampen IL-17A-driven inflammation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TICAM-1 (TRIF) is the TIR-domain adaptor that couples endosomal Toll-like receptor sensing of double-stranded RNA and LPS to type I interferon and inflammatory transcription, thereby orchestrating antiviral and antitumor innate immunity [#0, #1]. It is recruited to TLR3 by direct TIR-TIR interaction, while TLR4 signaling reaches TICAM-1 indirectly through the bridging adaptor TICAM-2 (TRAM), whose endosomal localization is essential for TLR4-driven IFN-\\u03b2 [#1, #8]. Signaling is gated at several levels: the N-terminal domain (residues 1\\u2013153) folds into an eight-helix, IFIT-like fold that auto-inhibits IFN-\\u03b2 and NF-\\u03baB output [#3], and full activation requires TRAF2 and TRAF6 binding to distinct N-terminal motifs to catalyze K63-linked ubiquitination of TICAM-1, driving IRF-3 and NF-\\u03baB activation [#2]. Productive signaling proceeds through assembly of a cytoplasmic TICAM-1 signalosome, which depends on 14-3-3-zeta for multimerization and is enhanced by the relocalized nuclear repressor BS69 [#4, #5]; for TLR4, Raftlin-dependent receptor endocytosis is specifically required for the TICAM-1 branch of IFN-\\u03b2 production [#6]. The pathway is terminated by lysosome-dependent degradation of TICAM-1 that desensitizes TLR3 [#7]. Genetically, TICAM-1 is required in dendritic cells for poly(I:C)-driven NK-cell activation, CD8\\u03b1+ DC cross-priming of antitumor CTLs, and host defense against poliovirus [#10, #11, #12]. Beyond TLR signaling, TICAM-1 also acts as a negative regulator of IL-17A responses by binding Act1 and competing with the IL-17RA\\u2013Act1 interaction [#9].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that a TIR adaptor distinct from MyD88 links TLR3 to interferon induction, defining the molecular basis of MyD88-independent antiviral signaling.\",\n      \"evidence\": \"Co-IP and IFN-\\u03b2 promoter reporter assays with poly(I:C) in human cells\",\n      \"pmids\": [\"12539043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve the downstream kinases or signalosome assembly\", \"Overexpression system may not reflect endogenous stoichiometry\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Explained how LPS-TLR4 reaches the same adaptor without direct binding, identifying TICAM-2 as the bridging adaptor that channels TLR4 into TICAM-1-dependent IFN-\\u03b2.\",\n      \"evidence\": \"Co-IP plus IFN-\\u03b2 and NF-\\u03baB reporter assays\",\n      \"pmids\": [\"14519765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the TICAM-2/TICAM-1 interface not resolved here\", \"Subcellular compartment of the bridge unaddressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that TICAM-1 is physiologically required in myeloid DCs for contact-dependent NK activation and antitumor responses, moving the adaptor from cytokine induction to cellular immunity.\",\n      \"evidence\": \"TICAM-1 knockout mice in B16 melanoma model with adoptive transfer and transwell analysis\",\n      \"pmids\": [\"17190817\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DC-NK contact signal molecularly undefined\", \"Single tumor model\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the ubiquitin-dependent activation step, showing TRAF2 and TRAF6 bind distinct N-terminal motifs and K63-ubiquitinate TICAM-1 to drive IRF-3/NF-\\u03baB output.\",\n      \"evidence\": \"Yeast two-hybrid, alanine-scan mutagenesis, in-cell ubiquitination and IFN-\\u03b2 reporter assays\",\n      \"pmids\": [\"20047764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DUBs that reverse the modification unknown\", \"Chain topology assignment relies on in-cell assays\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed that TICAM-1 signaling is self-limiting via lysosomal degradation, establishing a receptor desensitization mechanism for TLR3.\",\n      \"evidence\": \"Western blot of protein levels with lysosome/proteasome/caspase inhibitors and siRNA during dsRNA or rhinovirus stimulation\",\n      \"pmids\": [\"22205631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking machinery delivering TICAM-1 to lysosomes unidentified\", \"No degradation-resistant mutant tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed TICAM-1 is the dominant adaptor for antiviral protection in vivo, with TLR3-TICAM-1 outweighing the RIG-I/IPS-1 axis in poliovirus defense.\",\n      \"evidence\": \"TICAM-1 vs IPS-1 knockout in PVR-transgenic mice with IFN measurement\",\n      \"pmids\": [\"21998457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution may be virus-specific\", \"IFN source cells inferred from ex vivo analysis\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected TICAM-1 to adaptive immunity by showing it is required in CD8\\u03b1+ DCs for poly(I:C)-driven cross-priming of antigen-specific CTLs.\",\n      \"evidence\": \"TICAM-1 and IPS-1 knockout mice with tetramer and OT-1 proliferation assays in EG7 tumor model\",\n      \"pmids\": [\"22934250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking adaptor signaling to cross-presentation machinery undefined\", \"Single antigen model\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified BS69 as a cytoplasmic cofactor that promotes TICAM-1 signalosome (speckle) formation, beginning to explain how the adaptor oligomerizes for full activation.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, confocal imaging, and siRNA knockdown with reporter assays\",\n      \"pmids\": [\"19795416\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of nuclear-to-cytoplasmic relocation unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural basis for intramolecular regulation, showing the N-terminal IFIT-like helical domain auto-inhibits TICAM-1 signaling.\",\n      \"evidence\": \"2.22 \\u00c5 X-ray crystal structure of residues 1\\u2013153 with IFN-\\u03b2/NF-\\u03baB reporter validation\",\n      \"pmids\": [\"24311583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length or signalosome state not solved\", \"Trigger that relieves auto-inhibition unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established 14-3-3-zeta as a required factor for TICAM-1 multimerization, mechanistically linking signalosome assembly to downstream IRF-3/I\\u03baB activation.\",\n      \"evidence\": \"siRNA knockdown with multimerization, IRF-3 translocation, and cytokine readouts\",\n      \"pmids\": [\"27058640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect binding to TICAM-1 not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed that TLR4 endocytosis via Raftlin is selectively required for the TICAM-1/IFN-\\u03b2 branch but not NF-\\u03baB, explaining spatial control of adaptor usage.\",\n      \"evidence\": \"siRNA, Co-IP with TLR4/clathrin/AP-2, confocal imaging, and IFN-\\u03b2 readouts in human DCs/macrophages\",\n      \"pmids\": [\"27022195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct TICAM-1 engagement at endosome not shown\", \"Human myeloid cells only\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the molecular interface and compartment requirement for TLR4 signaling, mapping the TICAM-2 acidic motif that engages TICAM-1 and the endosomal localization needed for IFN.\",\n      \"evidence\": \"NMR structural analysis and mutagenesis of acidic motifs with IFN-\\u03b2 reporters\",\n      \"pmids\": [\"28630139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited primary experimental detail\", \"Reciprocal TICAM-1 interface residues not mapped here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Delimited the pathway specificity of TICAM-1 by showing it is dispensable for STING-driven IFN and DC maturation, distinguishing TLR3 from cytosolic DNA sensing.\",\n      \"evidence\": \"TICAM-1 knockout myeloid cells with cytokine mRNA and flow cytometry\",\n      \"pmids\": [\"29627569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result; does not exclude minor roles in other cell types\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Proposed a non-canonical role in directing TLR3-dependent sorting of miR-21 into extracellular vesicles.\",\n      \"evidence\": \"Ectopic overexpression and siRNA knockdown with EV miRNA quantification\",\n      \"pmids\": [\"29679565\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single approach with no sorting mechanism defined\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended TICAM-1 function beyond TLR signaling, showing it negatively regulates IL-17A responses by competing with the IL-17RA\\u2013Act1 interaction.\",\n      \"evidence\": \"Co-IP, TICAM-1 knockout mice, NF-\\u03baB/MAPK assays, and in vivo DTH/EAE models\",\n      \"pmids\": [\"34819358\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of TICAM-1/Act1 competition undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked TICAM-1 to intestinal tumor suppression in a microbiota-dependent manner, correlating its loss with accelerated, c-Myc-driven polyposis.\",\n      \"evidence\": \"TICAM-1 knockout in Apc Min/+ mice with immunofluorescence, RT-PCR, and survival analysis\",\n      \"pmids\": [\"29041928\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"c-Myc link is correlative\", \"dsRNA-producing bacterium not causally tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How auto-inhibition is relieved and the ubiquitinated, 14-3-3/BS69-assisted signalosome assembles into an active full-length structure remains structurally unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full-length or oligomeric structure\", \"Order and interdependence of ubiquitination, multimerization, and auto-inhibition relief unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 10, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 9]}\n    ],\n    \"complexes\": [\"TICAM-1 signalosome\"],\n    \"partners\": [\"TLR3\", \"TICAM2\", \"TRAF2\", \"TRAF6\", \"BS69\", \"YWHAZ\", \"TRAF3IP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}