{"gene":"TBKBP1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2011,"finding":"TBKBP1 (SINTBAD) competes with TANK and NAP1 for binding to TBK1, with the binding site for all three adaptors mapped to the C-terminal coiled-coil 2 region of TBK1; the three adaptors form mutually exclusive complexes with TBK1/IKK-i and reside in different subcellular locations.","method":"Affinity purification-mass spectrometry, competition binding assays, immunofluorescence, point mutagenesis of TBK1","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — systematic AP-MS network mapping combined with mutagenesis and cell reconstitution; multiple orthogonal methods in a single rigorous study","pmids":["21931631"],"is_preprint":false},{"year":2019,"finding":"TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) via the scaffold protein CARD10, enabling PKCθ to phosphorylate TBK1 at Ser716; this phosphorylation is required for TBK1 activation by growth factors but not by innate immune stimuli. The TBK1-TBKBP1 axis mediates mTORC1 activation, oncogenesis, PD-L1 induction, and glycolysis stimulation. Conditional deletion of either TBK1 or TBKBP1 in lung epithelial cells inhibits tumourigenesis in a mouse lung cancer model.","method":"Co-immunoprecipitation, conditional knockout mouse models, phospho-specific antibodies, in vivo tumour models, biochemical reconstitution","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, KO mouse, phospho-mutagenesis, in vivo tumour model) in a single rigorous study","pmids":["31792381"],"is_preprint":false},{"year":2018,"finding":"TBKBP1 facilitates IL-15-induced autophagy in NKT cells by antagonizing mTORC1 inhibitory action on the autophagy-initiating kinase ULK1, via recruitment of an mTORC1-opposing phosphatase to ULK1. Tbkbp1 deficiency impairs autophagy, causes mitochondrial dysfunction, aberrant ROS production, defective Bcl2 expression and reduced NKT (and NK) cell survival, resulting in profound NKT cell deficiency in vivo.","method":"Tbkbp1 knockout mice, autophagy assays, mitochondrial function assays, biochemical co-immunoprecipitation, flow cytometry","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotypes, multiple orthogonal biochemical methods, in vivo validation","pmids":["30022064"],"is_preprint":false},{"year":2019,"finding":"TBKBP1/SINTBAD forms a trimer with RB1CC1/FIP200 (ULK complex) and AZI2/NAP1 (TBK1 complex) bridged by the cargo receptor CALCOCO2/NDP52, thereby recruiting the upstream autophagy-initiating machinery to cargo-determined locations to initiate selective autophagy.","method":"Co-immunoprecipitation, selective autophagy reconstitution assays with Salmonella-containing vacuoles","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic complex formation demonstrated by Co-IP and functional reconstitution in a single lab","pmids":["31258038"],"is_preprint":false},{"year":2019,"finding":"TBKBP1/SINTBAD is incorporated into stress-induced cytosolic membraneless organelles termed SINT-speckles; deletion of SINTBAD together with AZI2 impairs TBK1 phosphorylation, and SINT-speckle formation is controlled positively by acetyltransferase KAT2A (GCN5) and negatively by ULK1/2 kinases and heat-shock chaperones.","method":"Proteomics-based interactome profiling, immunofluorescence microscopy, gene knockout/knockdown, TBK1 phosphorylation assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interactome mass spectrometry plus KO functional assays, single lab with multiple orthogonal methods","pmids":["31442668"],"is_preprint":false},{"year":2013,"finding":"TBKBP1 physically interacts with TBK1, demonstrated by tandem affinity purification from HEK-293T cell lysates, placing it as a direct binding partner in the TBK1 molecular complex alongside NAP1 and TANK.","method":"Tandem affinity purification followed by mass spectrometry (HEK-293T cells)","journal":"Current eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TAP-MS in a single lab; consistent with independently replicated findings in other studies","pmids":["23286385"],"is_preprint":false},{"year":2013,"finding":"AZI2 (NAP1), but not TBKBP1, is critical for GM-CSF-induced differentiation of conventional dendritic cells from bone marrow; neither AZI2 nor TBKBP1 is required for type I IFN production in response to viral infection in mice.","method":"AZI2-deficient mouse bone marrow-derived dendritic cell differentiation assays, viral infection assays, cytokine measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse model with defined negative result for TBKBP1 in IFN production; single lab","pmids":["23610142"],"is_preprint":false},{"year":2024,"finding":"TBKBP1/SINTBAD is recruited to damaged mitochondria during Parkin-mediated mitophagy but, unlike AZI2/NAP1, does not significantly impact NDP52-driven mitophagy; AZI2 (not TBKBP1) is the TBK1 adaptor required for NDP52-driven mitophagy.","method":"TBKBP1 and AZI2 knockout constructs combined with OPTN knockout, mitophagy assays, phospho-proteomics","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — series of KO constructs with defined negative result for TBKBP1 in NDP52-mitophagy; single lab","pmids":["39276928"],"is_preprint":false},{"year":2025,"finding":"TBK1 sustains the abundance and phosphorylation of its interacting adaptor proteins including TBKBP1/SINTBAD in human iPSC-derived neurons; loss of TBK1 reduces TBKBP1 levels and phosphorylation state as measured by global quantitative proteomics and phospho-proteomics.","method":"Isogenic iPSC lines with TBK1 loss-of-function, quantitative global proteomics and phospho-proteomics in stem cells and neurons","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative phospho-proteomics in isogenic human cell lines; single lab","pmids":["41171761"],"is_preprint":false},{"year":2009,"finding":"ProSAPiP2 (TBKBP1) binds to the PDZ domain of ProSAP2/Shank3, localizes to dendrites and spines, is enriched in the postsynaptic density (PSD), and interacts with actin, suggesting a role in linking PSD molecules to the actin cytoskeleton.","method":"Co-immunoprecipitation, immunofluorescence localization in neurons, subcellular fractionation (PSD enrichment), actin interaction assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct binding shown by Co-IP and PSD fractionation, localization confirmed by imaging; single lab with multiple methods","pmids":["19481056"],"is_preprint":false},{"year":2024,"finding":"TBKBP1 overexpression in CMV-specific CD8+ T cells enhances TBK1 phosphorylation upon stimulation and significantly improves virus neutralization capacity; TBKBP1 demethylation correlates with higher TBKBP1 mRNA and protein expression in terminal effector CD8+ T cells.","method":"TBKBP1 overexpression in primary human CD8+ T cells, phospho-TBK1 assays, virus neutralization assays, whole-genome bisulfite sequencing","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression with defined phosphorylation and functional readout; single lab, multiple orthogonal methods","pmids":["39325839"],"is_preprint":false},{"year":2024,"finding":"The MCV viral protein MC089 physically interacts with TBKBP1 (along with IKKε and NAP1) to inhibit IRF3 activation, specifically suppressing immunostimulatory nucleic acid-induced serine 396 phosphorylation of IRF3 without affecting serine 386 phosphorylation.","method":"Co-immunoprecipitation of MC089 with TBKBP1/IKKε/NAP1, IRF3 phosphorylation assays with phospho-specific antibodies","journal":"The Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct interaction demonstrated by Co-IP with functional phosphorylation readout; single lab","pmids":["39167082"],"is_preprint":false},{"year":2026,"finding":"TBKBP1 promotes capecitabine resistance in triple-negative breast cancer by negatively regulating the type I interferon pathway through autophagy-mediated protein degradation of TBK1.","method":"In vivo mouse models, autophagy assays, TBK1 protein level measurement, immune cell infiltration analysis","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic conclusion (autophagy-mediated TBK1 degradation) inferred from in vivo and cell models in a single study; limited mechanistic detail available from abstract","pmids":["41606294"],"is_preprint":false},{"year":2024,"finding":"CALCOCO2/NDP52-mediated inhibition of hepatitis B virus does not require the RB1CC1-CALCOCO2-TBKBP1-AZI2 complex; CALCOCO2 mutants abolishing this complex formation maintain antiviral activity against HBV through a RAB9-dependent lysosomal degradation pathway.","method":"CALCOCO2 complex-disrupting mutants, RAB9 co-immunoprecipitation, viral replication assays","journal":"Autophagy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — negative result for TBKBP1 complex in HBV context; single lab, single study","pmids":["38752371"],"is_preprint":false}],"current_model":"TBKBP1 (also known as SINTBAD/ProSAPiP2) is a multifunctional adaptor protein that interacts with TBK1 through the kinase's C-terminal coiled-coil 2 domain; in innate immune signaling it competes with TANK and NAP1 for TBK1 binding to form mutually exclusive complexes, and—together with AZI2/NAP1—assembles with CALCOCO2/NDP52 to recruit the ULK and TBK1 complexes for selective autophagy initiation; in growth factor signaling it acts as a scaffold that recruits TBK1 to PKCθ via CARD10, enabling PKCθ-mediated phosphorylation of TBK1 at Ser716 to drive mTORC1 activation, oncogenesis, PD-L1-mediated immunosuppression, and glycolysis; in NK/NKT cell biology it antagonizes mTORC1 inhibition of ULK1 to promote IL-15-induced autophagy and cell survival; and at excitatory synapses it binds the PDZ domain of ProSAP2/Shank3 and interacts with actin to link postsynaptic density components to the cytoskeleton."},"narrative":{"mechanistic_narrative":"TBKBP1 (SINTBAD/ProSAPiP2) is a multifunctional adaptor that organizes TBK1-centered signaling complexes across innate immunity, selective autophagy, growth-factor-driven oncogenesis, and synaptic architecture [PMID:21931631, PMID:31792381, PMID:31258038]. It binds TBK1 directly through the kinase's C-terminal coiled-coil 2 region, where it competes with the related adaptors TANK and NAP1/AZI2 to form mutually exclusive, differentially localized complexes [PMID:21931631, PMID:23286385]. In growth-factor signaling, TBKBP1 functions as a scaffold that recruits TBK1 to PKCθ via CARD10, enabling PKCθ-mediated phosphorylation of TBK1 at Ser716; this step drives TBK1 activation, mTORC1 activation, glycolysis, PD-L1 induction, and tumourigenesis, and conditional deletion of TBKBP1 in lung epithelium suppresses lung cancer in vivo [PMID:31792381]. In selective autophagy, TBKBP1 partners with AZI2/NAP1 and the FIP200/RB1CC1-containing ULK complex, bridged by the cargo receptor CALCOCO2/NDP52, to recruit autophagy-initiating machinery to cargo [PMID:31258038], and it assembles into stress-induced cytosolic SINT-speckles whose formation supports TBK1 phosphorylation and is controlled by KAT2A, ULK1/2, and chaperones [PMID:31442668]. TBKBP1 also promotes IL-15-induced autophagy and survival in NKT/NK cells by antagonizing mTORC1 inhibition of ULK1 [PMID:30022064]. Beyond TBK1 signaling, TBKBP1 binds the PDZ domain of ProSAP2/Shank3 and interacts with actin in the postsynaptic density, linking PSD components to the cytoskeleton [PMID:19481056].","teleology":[{"year":2009,"claim":"Established a non-immune role for TBKBP1 as a postsynaptic adaptor, the earliest functional context defined for the protein.","evidence":"Co-IP, neuronal immunofluorescence, PSD fractionation, and actin-interaction assays","pmids":["19481056"],"confidence":"Medium","gaps":["No structural basis for the PDZ/actin interactions","Functional consequence for synaptic transmission not tested","Relationship to TBK1 signaling at synapses unexplored"]},{"year":2011,"claim":"Defined how TBKBP1 docks onto TBK1 and distinguished it from related adaptors, showing TANK, NAP1, and SINTBAD form mutually exclusive complexes at TBK1's coiled-coil 2.","evidence":"AP-MS network mapping, competition binding, point mutagenesis of TBK1, and immunofluorescence","pmids":["21931631"],"confidence":"High","gaps":["Functional output of each distinct complex not resolved","Determinants of differential subcellular localization unknown"]},{"year":2013,"claim":"Independently confirmed the direct TBK1–TBKBP1 interaction and tested adaptor specificity in dendritic cell differentiation and antiviral IFN responses.","evidence":"TAP-MS in HEK-293T; AZI2-deficient mouse BMDC and viral infection assays","pmids":["23286385","23610142"],"confidence":"Medium","gaps":["TBKBP1 dispensable for type I IFN production, leaving its immune function undefined at this stage","No positive functional assay for TBKBP1 itself"]},{"year":2018,"claim":"Revealed a metabolic/survival function in lymphocytes, showing TBKBP1 enables IL-15-induced autophagy by relieving mTORC1 suppression of ULK1.","evidence":"Tbkbp1 knockout mice, autophagy and mitochondrial assays, Co-IP, flow cytometry","pmids":["30022064"],"confidence":"High","gaps":["Identity of the mTORC1-opposing phosphatase recruited to ULK1 not fully defined","Whether this pathway operates outside NKT/NK cells unclear"]},{"year":2019,"claim":"Connected TBKBP1 to oncogenic growth-factor signaling, defining the CARD10-PKCθ scaffold that phosphorylates TBK1 at Ser716 and drives mTORC1, PD-L1, glycolysis, and tumour growth.","evidence":"Co-IP, conditional KO mice, phospho-specific antibodies, in vivo lung tumour models, reconstitution","pmids":["31792381"],"confidence":"High","gaps":["Stimulus selectivity (growth factor vs innate) mechanism incompletely mapped","Downstream mTORC1 wiring partially defined"]},{"year":2019,"claim":"Placed TBKBP1 within the selective-autophagy initiation machinery and into stress-induced membraneless organelles, linking complex assembly to TBK1 activation.","evidence":"Co-IP, Salmonella-vacuole reconstitution; interactome proteomics, imaging, KO, TBK1 phosphorylation assays","pmids":["31258038","31442668"],"confidence":"Medium","gaps":["Single-lab reconstitution; in vivo relevance of SINT-speckles untested","Regulatory logic of KAT2A/ULK1/2 control of speckles incomplete"]},{"year":2024,"claim":"Clarified adaptor specificity within mitophagy and viral immune evasion, showing TBKBP1 is recruited to damaged mitochondria but is dispensable for NDP52-driven mitophagy, while being targeted by viral antagonists.","evidence":"TBKBP1/AZI2/OPTN KO mitophagy assays and phospho-proteomics; MC089 Co-IP and IRF3 phosphorylation assays","pmids":["39276928","39167082"],"confidence":"Medium","gaps":["Functional role of TBKBP1 recruitment to damaged mitochondria undefined","Mechanism of MC089-mediated S396-IRF3 suppression not fully resolved"]},{"year":2024,"claim":"Demonstrated TBKBP1 as a positive regulator of CD8+ T cell antiviral function and a TBK1-dependent stabilization substrate, tying its abundance to TBK1 activity.","evidence":"TBKBP1 overexpression in CD8+ T cells, phospho-TBK1 and neutralization assays, bisulfite sequencing; isogenic TBK1-LOF iPSC neuron proteomics","pmids":["39325839","41171761"],"confidence":"Medium","gaps":["Epigenetic control of TBKBP1 expression mechanistically thin","Reciprocal TBK1–TBKBP1 stabilization mechanism not defined"]},{"year":2026,"claim":"Extended TBKBP1's oncogenic relevance to therapy resistance, linking it to suppression of type I interferon via autophagy-mediated TBK1 degradation.","evidence":"In vivo mouse models, autophagy assays, TBK1 protein measurement, immune infiltration analysis","pmids":["41606294"],"confidence":"Low","gaps":["Autophagy-mediated TBK1 degradation mechanism inferred, not directly demonstrated","Reconciliation with TBKBP1's TBK1-activating roles in other contexts unresolved"]},{"year":null,"claim":"How TBKBP1's mutually exclusive adaptor complexes, subcellular targeting, and opposing effects on TBK1 (activation versus degradation) are selected in a given cellular context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of TBKBP1 in any complex","Switch between TBK1-stabilizing and TBK1-degrading functions undefined","Synaptic vs immune/autophagy roles not mechanistically integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1]}],"complexes":["ULK complex (FIP200/RB1CC1-AZI2-CALCOCO2-TBKBP1)","TBK1 adaptor complex","SINT-speckles","postsynaptic density"],"partners":["TBK1","AZI2","CALCOCO2","RB1CC1","CARD10","SHANK3","PRKCQ","ULK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A7MCY6","full_name":"TANK-binding kinase 1-binding protein 1","aliases":[],"length_aa":615,"mass_kda":67.7,"function":"Adapter protein which constitutively binds TBK1 and IKBKE playing a role in antiviral innate immunity","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/A7MCY6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TBKBP1","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MIF","stoichiometry":0.2},{"gene":"RBM14","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TBKBP1","total_profiled":1310},"omim":[{"mim_id":"608476","title":"TBK1-BINDING PROTEIN 1; TBKBP1","url":"https://www.omim.org/entry/608476"},{"mim_id":"604834","title":"TANK-BINDING KINASE 1; TBK1","url":"https://www.omim.org/entry/604834"},{"mim_id":"106300","title":"SPONDYLOARTHROPATHY, SUSCEPTIBILITY TO, 1; SPDA1","url":"https://www.omim.org/entry/106300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TBKBP1"},"hgnc":{"alias_symbol":["ProSAPiP2","KIAA0775"],"prev_symbol":[]},"alphafold":{"accession":"A7MCY6","domains":[{"cath_id":"-","chopping":"92-179_229-323","consensus_level":"medium","plddt":93.6245,"start":92,"end":323},{"cath_id":"1.20.5","chopping":"41-79","consensus_level":"medium","plddt":90.4115,"start":41,"end":79}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A7MCY6","model_url":"https://alphafold.ebi.ac.uk/files/AF-A7MCY6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A7MCY6-F1-predicted_aligned_error_v6.png","plddt_mean":63.41},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TBKBP1","jax_strain_url":"https://www.jax.org/strain/search?query=TBKBP1"},"sequence":{"accession":"A7MCY6","fasta_url":"https://rest.uniprot.org/uniprotkb/A7MCY6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A7MCY6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A7MCY6"}},"corpus_meta":[{"pmid":"24830394","id":"PMC_24830394","title":"Bayesian 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pathway.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/38752371","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.05.631349","title":"Absolute Quantification of Aging-Associated Glycans in IgG for Biological Age Prediction: Insights from Glycomics and Transcriptomics","date":"2025-01-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.05.631349","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17656,"output_tokens":3610,"usd":0.053559,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11106,"output_tokens":3599,"usd":0.072752,"stage2_stop_reason":"end_turn"},"total_usd":0.126311,"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\": 2011,\n      \"finding\": \"TBKBP1 (SINTBAD) competes with TANK and NAP1 for binding to TBK1, with the binding site for all three adaptors mapped to the C-terminal coiled-coil 2 region of TBK1; the three adaptors form mutually exclusive complexes with TBK1/IKK-i and reside in different subcellular locations.\",\n      \"method\": \"Affinity purification-mass spectrometry, competition binding assays, immunofluorescence, point mutagenesis of TBK1\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — systematic AP-MS network mapping combined with mutagenesis and cell reconstitution; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"21931631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) via the scaffold protein CARD10, enabling PKCθ to phosphorylate TBK1 at Ser716; this phosphorylation is required for TBK1 activation by growth factors but not by innate immune stimuli. The TBK1-TBKBP1 axis mediates mTORC1 activation, oncogenesis, PD-L1 induction, and glycolysis stimulation. Conditional deletion of either TBK1 or TBKBP1 in lung epithelial cells inhibits tumourigenesis in a mouse lung cancer model.\",\n      \"method\": \"Co-immunoprecipitation, conditional knockout mouse models, phospho-specific antibodies, in vivo tumour models, biochemical reconstitution\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, KO mouse, phospho-mutagenesis, in vivo tumour model) in a single rigorous study\",\n      \"pmids\": [\"31792381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TBKBP1 facilitates IL-15-induced autophagy in NKT cells by antagonizing mTORC1 inhibitory action on the autophagy-initiating kinase ULK1, via recruitment of an mTORC1-opposing phosphatase to ULK1. Tbkbp1 deficiency impairs autophagy, causes mitochondrial dysfunction, aberrant ROS production, defective Bcl2 expression and reduced NKT (and NK) cell survival, resulting in profound NKT cell deficiency in vivo.\",\n      \"method\": \"Tbkbp1 knockout mice, autophagy assays, mitochondrial function assays, biochemical co-immunoprecipitation, flow cytometry\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotypes, multiple orthogonal biochemical methods, in vivo validation\",\n      \"pmids\": [\"30022064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TBKBP1/SINTBAD forms a trimer with RB1CC1/FIP200 (ULK complex) and AZI2/NAP1 (TBK1 complex) bridged by the cargo receptor CALCOCO2/NDP52, thereby recruiting the upstream autophagy-initiating machinery to cargo-determined locations to initiate selective autophagy.\",\n      \"method\": \"Co-immunoprecipitation, selective autophagy reconstitution assays with Salmonella-containing vacuoles\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic complex formation demonstrated by Co-IP and functional reconstitution in a single lab\",\n      \"pmids\": [\"31258038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TBKBP1/SINTBAD is incorporated into stress-induced cytosolic membraneless organelles termed SINT-speckles; deletion of SINTBAD together with AZI2 impairs TBK1 phosphorylation, and SINT-speckle formation is controlled positively by acetyltransferase KAT2A (GCN5) and negatively by ULK1/2 kinases and heat-shock chaperones.\",\n      \"method\": \"Proteomics-based interactome profiling, immunofluorescence microscopy, gene knockout/knockdown, TBK1 phosphorylation assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interactome mass spectrometry plus KO functional assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31442668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TBKBP1 physically interacts with TBK1, demonstrated by tandem affinity purification from HEK-293T cell lysates, placing it as a direct binding partner in the TBK1 molecular complex alongside NAP1 and TANK.\",\n      \"method\": \"Tandem affinity purification followed by mass spectrometry (HEK-293T cells)\",\n      \"journal\": \"Current eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TAP-MS in a single lab; consistent with independently replicated findings in other studies\",\n      \"pmids\": [\"23286385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AZI2 (NAP1), but not TBKBP1, is critical for GM-CSF-induced differentiation of conventional dendritic cells from bone marrow; neither AZI2 nor TBKBP1 is required for type I IFN production in response to viral infection in mice.\",\n      \"method\": \"AZI2-deficient mouse bone marrow-derived dendritic cell differentiation assays, viral infection assays, cytokine measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse model with defined negative result for TBKBP1 in IFN production; single lab\",\n      \"pmids\": [\"23610142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TBKBP1/SINTBAD is recruited to damaged mitochondria during Parkin-mediated mitophagy but, unlike AZI2/NAP1, does not significantly impact NDP52-driven mitophagy; AZI2 (not TBKBP1) is the TBK1 adaptor required for NDP52-driven mitophagy.\",\n      \"method\": \"TBKBP1 and AZI2 knockout constructs combined with OPTN knockout, mitophagy assays, phospho-proteomics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — series of KO constructs with defined negative result for TBKBP1 in NDP52-mitophagy; single lab\",\n      \"pmids\": [\"39276928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TBK1 sustains the abundance and phosphorylation of its interacting adaptor proteins including TBKBP1/SINTBAD in human iPSC-derived neurons; loss of TBK1 reduces TBKBP1 levels and phosphorylation state as measured by global quantitative proteomics and phospho-proteomics.\",\n      \"method\": \"Isogenic iPSC lines with TBK1 loss-of-function, quantitative global proteomics and phospho-proteomics in stem cells and neurons\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative phospho-proteomics in isogenic human cell lines; single lab\",\n      \"pmids\": [\"41171761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ProSAPiP2 (TBKBP1) binds to the PDZ domain of ProSAP2/Shank3, localizes to dendrites and spines, is enriched in the postsynaptic density (PSD), and interacts with actin, suggesting a role in linking PSD molecules to the actin cytoskeleton.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization in neurons, subcellular fractionation (PSD enrichment), actin interaction assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct binding shown by Co-IP and PSD fractionation, localization confirmed by imaging; single lab with multiple methods\",\n      \"pmids\": [\"19481056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TBKBP1 overexpression in CMV-specific CD8+ T cells enhances TBK1 phosphorylation upon stimulation and significantly improves virus neutralization capacity; TBKBP1 demethylation correlates with higher TBKBP1 mRNA and protein expression in terminal effector CD8+ T cells.\",\n      \"method\": \"TBKBP1 overexpression in primary human CD8+ T cells, phospho-TBK1 assays, virus neutralization assays, whole-genome bisulfite sequencing\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression with defined phosphorylation and functional readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39325839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The MCV viral protein MC089 physically interacts with TBKBP1 (along with IKKε and NAP1) to inhibit IRF3 activation, specifically suppressing immunostimulatory nucleic acid-induced serine 396 phosphorylation of IRF3 without affecting serine 386 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation of MC089 with TBKBP1/IKKε/NAP1, IRF3 phosphorylation assays with phospho-specific antibodies\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct interaction demonstrated by Co-IP with functional phosphorylation readout; single lab\",\n      \"pmids\": [\"39167082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TBKBP1 promotes capecitabine resistance in triple-negative breast cancer by negatively regulating the type I interferon pathway through autophagy-mediated protein degradation of TBK1.\",\n      \"method\": \"In vivo mouse models, autophagy assays, TBK1 protein level measurement, immune cell infiltration analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic conclusion (autophagy-mediated TBK1 degradation) inferred from in vivo and cell models in a single study; limited mechanistic detail available from abstract\",\n      \"pmids\": [\"41606294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CALCOCO2/NDP52-mediated inhibition of hepatitis B virus does not require the RB1CC1-CALCOCO2-TBKBP1-AZI2 complex; CALCOCO2 mutants abolishing this complex formation maintain antiviral activity against HBV through a RAB9-dependent lysosomal degradation pathway.\",\n      \"method\": \"CALCOCO2 complex-disrupting mutants, RAB9 co-immunoprecipitation, viral replication assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — negative result for TBKBP1 complex in HBV context; single lab, single study\",\n      \"pmids\": [\"38752371\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TBKBP1 (also known as SINTBAD/ProSAPiP2) is a multifunctional adaptor protein that interacts with TBK1 through the kinase's C-terminal coiled-coil 2 domain; in innate immune signaling it competes with TANK and NAP1 for TBK1 binding to form mutually exclusive complexes, and—together with AZI2/NAP1—assembles with CALCOCO2/NDP52 to recruit the ULK and TBK1 complexes for selective autophagy initiation; in growth factor signaling it acts as a scaffold that recruits TBK1 to PKCθ via CARD10, enabling PKCθ-mediated phosphorylation of TBK1 at Ser716 to drive mTORC1 activation, oncogenesis, PD-L1-mediated immunosuppression, and glycolysis; in NK/NKT cell biology it antagonizes mTORC1 inhibition of ULK1 to promote IL-15-induced autophagy and cell survival; and at excitatory synapses it binds the PDZ domain of ProSAP2/Shank3 and interacts with actin to link postsynaptic density components to the cytoskeleton.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TBKBP1 (SINTBAD/ProSAPiP2) is a multifunctional adaptor that organizes TBK1-centered signaling complexes across innate immunity, selective autophagy, growth-factor-driven oncogenesis, and synaptic architecture [#0, #1, #3]. It binds TBK1 directly through the kinase's C-terminal coiled-coil 2 region, where it competes with the related adaptors TANK and NAP1/AZI2 to form mutually exclusive, differentially localized complexes [#0, #5]. In growth-factor signaling, TBKBP1 functions as a scaffold that recruits TBK1 to PKC\\u03b8 via CARD10, enabling PKC\\u03b8-mediated phosphorylation of TBK1 at Ser716; this step drives TBK1 activation, mTORC1 activation, glycolysis, PD-L1 induction, and tumourigenesis, and conditional deletion of TBKBP1 in lung epithelium suppresses lung cancer in vivo [#1]. In selective autophagy, TBKBP1 partners with AZI2/NAP1 and the FIP200/RB1CC1-containing ULK complex, bridged by the cargo receptor CALCOCO2/NDP52, to recruit autophagy-initiating machinery to cargo [#3], and it assembles into stress-induced cytosolic SINT-speckles whose formation supports TBK1 phosphorylation and is controlled by KAT2A, ULK1/2, and chaperones [#4]. TBKBP1 also promotes IL-15-induced autophagy and survival in NKT/NK cells by antagonizing mTORC1 inhibition of ULK1 [#2]. Beyond TBK1 signaling, TBKBP1 binds the PDZ domain of ProSAP2/Shank3 and interacts with actin in the postsynaptic density, linking PSD components to the cytoskeleton [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established a non-immune role for TBKBP1 as a postsynaptic adaptor, the earliest functional context defined for the protein.\",\n      \"evidence\": \"Co-IP, neuronal immunofluorescence, PSD fractionation, and actin-interaction assays\",\n      \"pmids\": [\"19481056\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for the PDZ/actin interactions\", \"Functional consequence for synaptic transmission not tested\", \"Relationship to TBK1 signaling at synapses unexplored\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined how TBKBP1 docks onto TBK1 and distinguished it from related adaptors, showing TANK, NAP1, and SINTBAD form mutually exclusive complexes at TBK1's coiled-coil 2.\",\n      \"evidence\": \"AP-MS network mapping, competition binding, point mutagenesis of TBK1, and immunofluorescence\",\n      \"pmids\": [\"21931631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional output of each distinct complex not resolved\", \"Determinants of differential subcellular localization unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Independently confirmed the direct TBK1\\u2013TBKBP1 interaction and tested adaptor specificity in dendritic cell differentiation and antiviral IFN responses.\",\n      \"evidence\": \"TAP-MS in HEK-293T; AZI2-deficient mouse BMDC and viral infection assays\",\n      \"pmids\": [\"23286385\", \"23610142\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TBKBP1 dispensable for type I IFN production, leaving its immune function undefined at this stage\", \"No positive functional assay for TBKBP1 itself\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a metabolic/survival function in lymphocytes, showing TBKBP1 enables IL-15-induced autophagy by relieving mTORC1 suppression of ULK1.\",\n      \"evidence\": \"Tbkbp1 knockout mice, autophagy and mitochondrial assays, Co-IP, flow cytometry\",\n      \"pmids\": [\"30022064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the mTORC1-opposing phosphatase recruited to ULK1 not fully defined\", \"Whether this pathway operates outside NKT/NK cells unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected TBKBP1 to oncogenic growth-factor signaling, defining the CARD10-PKC\\u03b8 scaffold that phosphorylates TBK1 at Ser716 and drives mTORC1, PD-L1, glycolysis, and tumour growth.\",\n      \"evidence\": \"Co-IP, conditional KO mice, phospho-specific antibodies, in vivo lung tumour models, reconstitution\",\n      \"pmids\": [\"31792381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stimulus selectivity (growth factor vs innate) mechanism incompletely mapped\", \"Downstream mTORC1 wiring partially defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed TBKBP1 within the selective-autophagy initiation machinery and into stress-induced membraneless organelles, linking complex assembly to TBK1 activation.\",\n      \"evidence\": \"Co-IP, Salmonella-vacuole reconstitution; interactome proteomics, imaging, KO, TBK1 phosphorylation assays\",\n      \"pmids\": [\"31258038\", \"31442668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab reconstitution; in vivo relevance of SINT-speckles untested\", \"Regulatory logic of KAT2A/ULK1/2 control of speckles incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Clarified adaptor specificity within mitophagy and viral immune evasion, showing TBKBP1 is recruited to damaged mitochondria but is dispensable for NDP52-driven mitophagy, while being targeted by viral antagonists.\",\n      \"evidence\": \"TBKBP1/AZI2/OPTN KO mitophagy assays and phospho-proteomics; MC089 Co-IP and IRF3 phosphorylation assays\",\n      \"pmids\": [\"39276928\", \"39167082\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of TBKBP1 recruitment to damaged mitochondria undefined\", \"Mechanism of MC089-mediated S396-IRF3 suppression not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated TBKBP1 as a positive regulator of CD8+ T cell antiviral function and a TBK1-dependent stabilization substrate, tying its abundance to TBK1 activity.\",\n      \"evidence\": \"TBKBP1 overexpression in CD8+ T cells, phospho-TBK1 and neutralization assays, bisulfite sequencing; isogenic TBK1-LOF iPSC neuron proteomics\",\n      \"pmids\": [\"39325839\", \"41171761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Epigenetic control of TBKBP1 expression mechanistically thin\", \"Reciprocal TBK1\\u2013TBKBP1 stabilization mechanism not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended TBKBP1's oncogenic relevance to therapy resistance, linking it to suppression of type I interferon via autophagy-mediated TBK1 degradation.\",\n      \"evidence\": \"In vivo mouse models, autophagy assays, TBK1 protein measurement, immune infiltration analysis\",\n      \"pmids\": [\"41606294\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Autophagy-mediated TBK1 degradation mechanism inferred, not directly demonstrated\", \"Reconciliation with TBKBP1's TBK1-activating roles in other contexts unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TBKBP1's mutually exclusive adaptor complexes, subcellular targeting, and opposing effects on TBK1 (activation versus degradation) are selected in a given cellular context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of TBKBP1 in any complex\", \"Switch between TBK1-stabilizing and TBK1-degrading functions undefined\", \"Synaptic vs immune/autophagy roles not mechanistically integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:9612973\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"ULK complex (FIP200/RB1CC1-AZI2-CALCOCO2-TBKBP1)\",\n      \"TBK1 adaptor complex\",\n      \"SINT-speckles\",\n      \"postsynaptic density\"\n    ],\n    \"partners\": [\n      \"TBK1\",\n      \"AZI2\",\n      \"CALCOCO2\",\n      \"RB1CC1\",\n      \"CARD10\",\n      \"SHANK3\",\n      \"PRKCQ\",\n      \"ULK1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}