Affinage

TBKBP1

TANK-binding kinase 1-binding protein 1 · UniProt A7MCY6

Length
615 aa
Mass
67.7 kDa
Annotated
2026-06-10
29 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2009 Medium

    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

    PMID:19481056

    Open questions at the time
    • No structural basis for the PDZ/actin interactions
    • Functional consequence for synaptic transmission not tested
    • Relationship to TBK1 signaling at synapses unexplored
  2. 2011 High

    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

    PMID:21931631

    Open questions at the time
    • Functional output of each distinct complex not resolved
    • Determinants of differential subcellular localization unknown
  3. 2013 Medium

    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

    PMID:23286385 PMID:23610142

    Open questions at the time
    • TBKBP1 dispensable for type I IFN production, leaving its immune function undefined at this stage
    • No positive functional assay for TBKBP1 itself
  4. 2018 High

    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

    PMID:30022064

    Open questions at the time
    • Identity of the mTORC1-opposing phosphatase recruited to ULK1 not fully defined
    • Whether this pathway operates outside NKT/NK cells unclear
  5. 2019 High

    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

    PMID:31792381

    Open questions at the time
    • Stimulus selectivity (growth factor vs innate) mechanism incompletely mapped
    • Downstream mTORC1 wiring partially defined
  6. 2019 Medium

    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

    PMID:31258038 PMID:31442668

    Open questions at the time
    • Single-lab reconstitution; in vivo relevance of SINT-speckles untested
    • Regulatory logic of KAT2A/ULK1/2 control of speckles incomplete
  7. 2024 Medium

    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

    PMID:39167082 PMID:39276928

    Open questions at the time
    • Functional role of TBKBP1 recruitment to damaged mitochondria undefined
    • Mechanism of MC089-mediated S396-IRF3 suppression not fully resolved
  8. 2024 Medium

    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

    PMID:39325839 PMID:41171761

    Open questions at the time
    • Epigenetic control of TBKBP1 expression mechanistically thin
    • Reciprocal TBK1–TBKBP1 stabilization mechanism not defined
  9. 2026 Low

    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

    PMID:41606294

    Open questions at the time
    • Autophagy-mediated TBK1 degradation mechanism inferred, not directly demonstrated
    • Reconciliation with TBKBP1's TBK1-activating roles in other contexts unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005739 mitochondrion 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-9612973 Autophagy 3 R-HSA-168256 Immune System 2 R-HSA-162582 Signal Transduction 1
Partners
AZI2CALCOCO2CARD10PRKCQRB1CC1SHANK3TBK1ULK1
Complex memberships
SINT-specklesTBK1 adaptor complexULK complex (FIP200/RB1CC1-AZI2-CALCOCO2-TBKBP1)postsynaptic density

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 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. Affinity purification-mass spectrometry, competition binding assays, immunofluorescence, point mutagenesis of TBK1 PloS one High 21931631
2019 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. Co-immunoprecipitation, conditional knockout mouse models, phospho-specific antibodies, in vivo tumour models, biochemical reconstitution Nature cell biology High 31792381
2018 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. Tbkbp1 knockout mice, autophagy assays, mitochondrial function assays, biochemical co-immunoprecipitation, flow cytometry Nature communications High 30022064
2019 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. Co-immunoprecipitation, selective autophagy reconstitution assays with Salmonella-containing vacuoles Autophagy Medium 31258038
2019 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. Proteomics-based interactome profiling, immunofluorescence microscopy, gene knockout/knockdown, TBK1 phosphorylation assays iScience Medium 31442668
2013 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. Tandem affinity purification followed by mass spectrometry (HEK-293T cells) Current eye research Medium 23286385
2013 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. AZI2-deficient mouse bone marrow-derived dendritic cell differentiation assays, viral infection assays, cytokine measurement Journal of immunology Medium 23610142
2024 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. TBKBP1 and AZI2 knockout constructs combined with OPTN knockout, mitophagy assays, phospho-proteomics The Journal of biological chemistry Medium 39276928
2025 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. Isogenic iPSC lines with TBK1 loss-of-function, quantitative global proteomics and phospho-proteomics in stem cells and neurons Cell reports Medium 41171761
2009 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. Co-immunoprecipitation, immunofluorescence localization in neurons, subcellular fractionation (PSD enrichment), actin interaction assays Biochemical and biophysical research communications Medium 19481056
2024 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. TBKBP1 overexpression in primary human CD8+ T cells, phospho-TBK1 assays, virus neutralization assays, whole-genome bisulfite sequencing PLoS pathogens Medium 39325839
2024 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. Co-immunoprecipitation of MC089 with TBKBP1/IKKε/NAP1, IRF3 phosphorylation assays with phospho-specific antibodies The Journal of general virology Medium 39167082
2026 TBKBP1 promotes capecitabine resistance in triple-negative breast cancer by negatively regulating the type I interferon pathway through autophagy-mediated protein degradation of TBK1. In vivo mouse models, autophagy assays, TBK1 protein level measurement, immune cell infiltration analysis Oncogene Low 41606294
2024 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. CALCOCO2 complex-disrupting mutants, RAB9 co-immunoprecipitation, viral replication assays Autophagy Low 38752371

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS genetics 3109 24830394
2011 Functional dissection of the TBK1 molecular network. PloS one 119 21931631
2018 Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies. PLoS medicine 117 29315334
2022 Regulation of IRF3 activation in human antiviral signaling pathways. Biochemical pharmacology 107 35367198
2020 The landscape of host genetic factors involved in immune response to common viral infections. Genome medicine 96 33109261
2019 TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis. Nature cell biology 77 31792381
2018 TBK-binding protein 1 regulates IL-15-induced autophagy and NKT cell survival. Nature communications 34 30022064
2015 Genetic loci that regulate ectopic calcification in response to knee trauma in LG/J by SM/J advanced intercross mice. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 31 25989359
2019 CALCOCO2/NDP52 initiates selective autophagy through recruitment of ULK and TBK1 kinase complexes. Autophagy 21 31258038
2019 miR29a and miR378b Influence CpG-Stimulated Dendritic Cells and Regulate cGAS/STING Pathway. Vaccines 21 31779082
2020 The landscape of host genetic factors involved in immune response to common viral infections. medRxiv : the preprint server for health sciences 20 32511533
2013 Critical role of AZI2 in GM-CSF-induced dendritic cell differentiation. Journal of immunology (Baltimore, Md. : 1950) 20 23610142
2009 ProSAPiP2, a novel postsynaptic density protein that interacts with ProSAP2/Shank3. Biochemical and biophysical research communications 17 19481056
2023 Exploring the mediation of DNA methylation across the epigenome between childhood adversity and First Episode of Psychosis-findings from the EU-GEI study. Molecular psychiatry 16 37062770
2019 ULK1/2 Restricts the Formation of Inducible SINT-Speckles, Membraneless Organelles Controlling the Threshold of TBK1 Activation. iScience 14 31442668
2024 Genome-wide meta-analysis identifies 22 loci for normal tension glaucoma with significant overlap with high tension glaucoma. Nature communications 10 39551815
2024 TBK1 adaptor AZI2/NAP1 regulates NDP52-driven mitochondrial autophagy. The Journal of biological chemistry 7 39276928
2019 Analysis of 47 Non-MHC Ankylosing Spondylitis Susceptibility Loci Regarding Associated Variants across Whites and Han Chinese. The Journal of rheumatology 7 31523044
2013 Identification of proteins that interact with TANK binding kinase 1 and testing for mutations associated with glaucoma. Current eye research 7 23286385
2015 Analysis of clinical indexes and RUNX3, TBKBP1, PPARGC1B polymorphisms in Chinese Han patients with ankylosing spondylitis. Genetic testing and molecular biomarkers 6 25494292
2014 Transcript co-variance with Nestin in two mouse genetic reference populations identifies Lef1 as a novel candidate regulator of neural precursor cell proliferation in the adult hippocampus. Frontiers in neuroscience 6 25565948
2022 A multi-step genomic approach prioritized TBKBP1 gene as relevant for multiple sclerosis susceptibility. Journal of neurology 5 35545683
2024 DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells. PLoS pathogens 3 39325839
2025 Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-associated autophagy networks. Cell reports 2 41171761
2024 Blood transcriptome analysis uncovered COVID-19-myocarditis crosstalk. Microbial pathogenesis 1 38373644
2024 Molluscum contagiosum virus protein MC089 inhibits interferon regulatory factor 3 activation. The Journal of general virology 1 39167082
2026 TBKBP1 induces capecitabine resistance through negative regulation of type I interferon pathway in triple-negative breast cancer. Oncogene 0 41606294
2026 Ultrasound Activates TRPA1/TBKBP1 Signaling to Modulate Macrophage Polarization in Atherosclerosis: Insights From Bioinformatics and Functional Analysis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41930631
2024 CALCOCO2/NDP52 associates with RAB9 to initiate an antiviral response to hepatitis B virus infection through a lysosomal degradation pathway. Autophagy 0 38752371

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