Affinage

TBK1

Serine/threonine-protein kinase TBK1 · UniProt Q9UHD2

Length
729 aa
Mass
83.6 kDa
Annotated
2026-04-28
100 papers in source corpus 46 papers cited in narrative 46 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TBK1 is a serine/threonine kinase that serves as a central signaling hub integrating innate immune signaling, selective autophagy, cell death regulation, and metabolic control. In innate immunity, TBK1 is recruited to adaptor platforms—STING at the trans-Golgi network, MAVS via TRAFs, and NDP52—where it phosphorylates IRF3 to drive type I interferon production, with its activation enhanced by PRMT1-mediated arginine methylation, PTK2B-mediated Tyr591 phosphorylation, and regulated by SIRT5-dependent desuccinylation and K48/K27-linked ubiquitination (PMID:12692549, PMID:22394562, PMID:30842653, PMID:34551290, PMID:37989995, PMID:39673708, PMID:34257412). In selective autophagy and mitophagy, TBK1 phosphorylates autophagy receptors OPTN (S177) and p62 (S403), regulators Syntaxin 17 (S202), RAB7A (S72), and ULK1 complex components, with NDP52 and OPTN serving as cargo-proximal platforms for TBK1 recruitment and feed-forward activation (PMID:30853401, PMID:30827897, PMID:30627666, PMID:38287189, PMID:38918639). TBK1 also phosphorylates RIPK1 within the TNFR1 complex to suppress TNF-induced cell death, phosphorylates mTOR (S2159) to activate mTORC2-Akt signaling, inhibits AMPK in adipocytes, phosphorylates exocyst subunit Exo84 to facilitate insulin-stimulated GLUT4 trafficking, and limits NLRP3 inflammasome activation; loss-of-function mutations in TBK1 cause familial amyotrophic lateral sclerosis through disruption of optineurin binding, kinase activity, and mitophagy (PMID:30146158, PMID:30420664, PMID:34245780, PMID:29425491, PMID:28325821, PMID:34518217, PMID:25803835, PMID:34099552).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 High

    Establishing TBK1 as a kinase upstream of NF-κB resolved how growth factor and PKCε signals activate the IKK complex — TBK1 directly phosphorylates IKKβ to trigger IκB degradation.

    Evidence In vitro kinase assay, co-immunoprecipitation, and dominant-negative overexpression in mammalian cell lines

    PMID:10783893

    Open questions at the time
    • Whether TBK1 phosphorylation of IKKβ is the dominant route to NF-κB in all cell types
    • Structural basis of TBK1-IKKβ interaction not defined
  2. 2003 High

    Identifying TBK1 as the essential IRF3 kinase downstream of TLR3/dsRNA answered how the innate immune system links pathogen detection to interferon gene induction.

    Evidence Genetic epistasis, kinase assays, and loss-of-function studies in cell lines

    PMID:12692549

    Open questions at the time
    • How TBK1 achieves substrate specificity for IRF3 versus NF-κB was unresolved
    • Redundancy with IKKε was not fully delineated
  3. 2012 High

    Demonstrating that STING acts as a scaffold that recruits both TBK1 and IRF3, with separable binding sites, explained how substrate specificity is enforced — STING presents IRF3 to TBK1 rather than TBK1 finding IRF3 freely.

    Evidence In vitro reconstitution with mutagenesis and co-immunoprecipitation

    PMID:22394562

    Open questions at the time
    • Atomic-resolution structure of the STING-TBK1-IRF3 ternary complex was still lacking
    • Whether other adaptors enforce specificity by similar scaffolding was unknown
  4. 2015 High

    Discovery that TBK1 loss-of-function mutations cause familial ALS, with CCD2 domain mutations specifically disrupting optineurin binding, established a direct genetic link between TBK1-dependent autophagy and neurodegeneration.

    Evidence Exome sequencing in ALS families, co-immunoprecipitation, linkage analysis

    PMID:25803835

    Open questions at the time
    • Which TBK1 substrates are most critical for motor neuron survival
    • Whether haploinsufficiency or dominant-negative effects drive disease
  5. 2017 High

    Multiple studies revealed TBK1's role in selective autophagy execution: TRIM23 K27-ubiquitination activates TBK1 dimerization for p62 phosphorylation, TRAFs bridge MAVS to TBK1's SDD domain, and TBK1 phosphorylates exocyst subunit Exo84 for insulin-stimulated GLUT4 trafficking — collectively establishing TBK1 as a multi-pathway kinase recruited by diverse adaptors.

    Evidence RNAi screens, in vitro kinase assays, mutagenesis, adipocyte KO, TRAF quadruple KO cells

    PMID:28325821 PMID:28871090 PMID:29125880

    Open questions at the time
    • How TBK1 discriminates among its many adaptor-dependent activation modes in a single cell
    • Structural basis of TBK1-TRAF SDD domain interaction
  6. 2018 High

    TBK1 was established as a checkpoint kinase preventing TNF-induced cell death: TBK1 phosphorylates RIPK1 within the TNFR1 complex via NEMO/TANK/NAP1 recruitment, and Tbk1−/− embryonic lethality is rescued by RIPK1 kinase-dead alleles, revealing a non-immune survival function.

    Evidence Genetic epistasis with double-mutant rescue in mice, co-immunoprecipitation, in vivo TNF-shock model

    PMID:30146158 PMID:30420664

    Open questions at the time
    • Specific RIPK1 phosphorylation sites targeted by TBK1 in vivo not fully mapped
    • Relative contribution of TBK1 vs IKKε in different tissues
  7. 2018 High

    TBK1 was shown to directly inhibit AMPK in adipocytes and to phosphorylate RAB7A at Ser72 during mitophagy, expanding TBK1's role to metabolic regulation and mitophagy substrate recruitment beyond autophagy receptors.

    Evidence Adipocyte-specific TBK1 KO mice, global phosphoproteomics, in vitro kinase assays

    PMID:29425491 PMID:30627666

    Open questions at the time
    • Mechanism by which TBK1 inhibits AMPK catalytic activity not structurally defined
    • Whether RAB7A S72 phosphorylation is relevant in non-mitophagy contexts
  8. 2019 High

    A cryo-EM structure of the TBK1-STING-cGAMP complex revealed that STING's C-terminal tail inserts as a β-strand between TBK1 subunits, and that STING phosphorylation requires oligomerization of both proteins — resolving how STING activation is coupled to signal amplification.

    Evidence Cryo-EM at near-atomic resolution with mutagenesis validation

    PMID:30842653

    Open questions at the time
    • Full-length STING-TBK1-IRF3 ternary complex structure not yet captured
    • How oligomeric state is controlled in native membranes
  9. 2019 High

    TBK1 was placed at the apex of autophagosome biogenesis through phosphorylation of Syntaxin 17 (Ser202) and ULK1 complex components via NDP52 recruitment, independent of canonical AMPK/mTOR regulation — defining a cargo-proximal autophagy initiation mechanism.

    Evidence Chemically inducible dimerization, CRISPR KO, live imaging, phospho-site mapping

    PMID:30827897 PMID:30853401

    Open questions at the time
    • Complete set of ULK1 complex sites phosphorylated by TBK1 not catalogued
    • Relative contribution of Stx17 vs direct ULK1 complex phosphorylation to autophagy initiation
  10. 2019 High

    Feed-forward TBK1 activation at mitophagy contact sites was demonstrated: OPTN bridges ubiquitinated mitochondria to pre-autophagosomal membranes, assembling a platform for TBK1 trans-autophosphorylation; PINK1/Parkin-driven mitophagy sequesters TBK1 from centrosomes, linking mitophagy to cell cycle control.

    Evidence Live imaging, CRISPR KO, engineered monobody inhibitors, PINK1/Parkin genetic interaction analysis

    PMID:31577952 PMID:38287189

    Open questions at the time
    • Structural basis of TBK1 trans-autophosphorylation within the OPTN complex
    • Physiological relevance of centrosomal TBK1 depletion during mitophagy in vivo
  11. 2020 High

    TBK1 and IKKε were shown to act redundantly for STING-dependent NF-κB but non-redundantly for IRF3 activation, resolving longstanding confusion about their relative contributions; simultaneously, TBK1 was found to phosphorylate DRP1 to prevent mitochondrial fission, preserving MAVS aggregation platforms.

    Evidence TBK1/IKKε single and double KO cells and mice; in vitro DRP1 kinase assay with knock-in models

    PMID:32268090 PMID:33171123

    Open questions at the time
    • Whether TBK1-DRP1 phosphorylation has non-immune roles in mitochondrial dynamics
    • How pathway-specific TBK1 vs IKKε usage is determined in vivo
  12. 2021 High

    Post-translational regulation of TBK1 was expanded: PRMT1 asymmetric dimethylation at R54/R134/R228 enhances TBK1 oligomerization; NEDD4 K27-linked ubiquitination at K344 targets TBK1 for NDP52-mediated autophagic degradation; and SIRT5 desuccinylation controls TBK1-IRF3 and TBK1-TRAF2 binding — establishing PTMs as critical modulators of TBK1 signaling amplitude.

    Evidence In vitro methylation and ubiquitination assays, site-directed mutagenesis, myeloid KO mice, adoptive macrophage transfer

    PMID:34257412 PMID:34551290 PMID:39673708

    Open questions at the time
    • Crosstalk between succinylation, methylation, and ubiquitination of TBK1 is unexplored
    • Whether autophagic degradation of TBK1 is a general feedback or context-specific
  13. 2021 High

    STING knock-in mice separating TBK1-binding (L373A) from IRF3-binding (S365A) functions demonstrated that TBK1 recruitment to STING drives NF-κB-dependent autoinflammatory arthritis independently of IRF3, redefining STING-TBK1 as a bifunctional signaling axis.

    Evidence STING knock-in point mutant mice in DNase II−/− background, cytokine profiling

    PMID:34901991

    Open questions at the time
    • Downstream TBK1 substrates mediating STING-dependent NF-κB activation independent of IRF3 are undefined
    • Relevance to human autoinflammatory disease
  14. 2021 High

    TBK1 was found to phosphorylate mTOR at S2159 within mTORC2, increasing mTORC2 catalytic activity and Akt phosphorylation, and to phosphorylate mutant huntingtin at S13 to reduce aggregation — revealing growth-signaling and neuroprotective substrate diversity beyond immunity and autophagy.

    Evidence In vitro kinase assays, Mtor S2159A knock-in mice, huntingtin phosphorylation validated in C. elegans and primary neurons

    PMID:32757223 PMID:34245780

    Open questions at the time
    • Which upstream signals activate TBK1 specifically toward mTORC2
    • Whether TBK1-mediated mHTT phosphorylation is therapeutically exploitable
  15. 2023 High

    PTK2B was identified as a tyrosine kinase that directly phosphorylates TBK1 at Tyr591 to promote TBK1 oligomerization and activation, adding a tyrosine-phosphorylation layer to TBK1 regulation and connecting innate immunity to calcium/integrin signaling.

    Evidence In vitro phosphorylation assay, CRISPR KO, Ptk2b-deficient mice with viral infection

    PMID:37989995

    Open questions at the time
    • Whether Tyr591 phosphorylation is pathway-selective (innate immune vs autophagy)
    • Structural consequence of Tyr591 phosphorylation on TBK1 dimer interface
  16. 2024 High

    The TBK1 adaptors NAP1 and SINTBAD were shown to compete with OPTN for TBK1 binding while simultaneously promoting NDP52-driven mitophagy, revealing that adaptor competition tunes TBK1 allocation between parallel selective autophagy pathways.

    Evidence Co-immunoprecipitation, CRISPR KO of NAP1/SINTBAD, selective autophagy and live-imaging assays

    PMID:38918639

    Open questions at the time
    • Quantitative stoichiometry of adaptor competition under physiological conditions
    • Whether adaptor competition is regulated by upstream signals

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how TBK1 substrate selection is determined when multiple adaptor platforms co-exist in the same cell, the full structural basis of TBK1 trans-autophosphorylation within signaling condensates, and whether therapeutic modulation of specific TBK1 signaling arms is achievable without disrupting others.
  • No structural model of TBK1 within an active signaling condensate
  • Pathway-selective TBK1 inhibitors have not been developed
  • In vivo contribution of individual PTMs (methylation, succinylation, ubiquitination) to TBK1 pathway selectivity is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 15 GO:0016740 transferase activity 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005739 mitochondrion 4 GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-168256 Immune System 11 R-HSA-9612973 Autophagy 11 R-HSA-162582 Signal Transduction 6 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3
Partners
IRF3NAP1NDP52OPTNPRMT1PTK2BRIPK1STING
Complex memberships
NDP52-TBK1-FIP200 complexSTING-TBK1 signalosomeTBK1-IKKε complex

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 TBK1 and IKKε are essential kinases in the IRF3 signaling pathway downstream of TLR3 and viral dsRNA, coordinating activation of both IRF3 and NF-κB in the innate immune response. Genetic epistasis, kinase assays, loss-of-function studies in cell lines Nature immunology High 12692549
2000 TBK1 (NAK) activates IKK through direct phosphorylation of IKKβ, thereby inducing IκB degradation and NF-κB activation downstream of PKCε and growth factors. In vitro kinase assay, co-immunoprecipitation, dominant-negative overexpression Nature High 10783893
2012 STING functions as a scaffold protein to recruit both TBK1 and IRF3, specifying IRF3 phosphorylation by TBK1; the C-terminal tail of STING is necessary and sufficient to activate TBK1, and STING mutations that selectively disrupt IRF3 binding abrogate IRF3 phosphorylation without impairing TBK1 activation. In vitro reconstitution system, mutagenesis, co-immunoprecipitation Science signaling High 22394562
2019 Cryo-EM structure of TBK1 in complex with cGAMP-bound full-length STING reveals the STING C-terminal tail inserts as a β-strand into a groove between the kinase domain of one TBK1 subunit and the scaffold/dimerization domain of the second; STING phosphorylation at Ser366 requires oligomerization of both STING and TBK1, validated by mutagenesis. Cryo-EM structure determination, mutational analysis Nature High 30842653
2009 TBK1 is selectively essential in KRAS-mutant cancer cells; TBK1 activates NF-κB anti-apoptotic signals (via c-Rel and BCL-XL) that are required for survival of KRAS-dependent cancer cells, and TBK1 suppression induces apoptosis specifically in these cells. Systematic RNAi screen, loss-of-function apoptosis assays, mechanistic follow-up with NF-κB pathway analysis Nature High 19847166
2018 TBK1 is an endogenous inhibitor of RIPK1 kinase; embryonic lethality of Tbk1-/- mice is rescued by inactivation of RIPK1, demonstrating TBK1 suppresses RIPK1-driven apoptosis during development. Genetic epistasis (double-mutant rescue), in vivo mouse models Cell High 30146158
2018 TBK1 and IKKε phosphorylate RIPK1 within the TNFR1 signaling complex (recruited via LUBAC-dependent linear ubiquitin and NEMO/TANK/NAP1), preventing RIPK1-dependent cell death; NEMO recruits TBK1/IKKε via TANK and NAP1 adaptors. Co-immunoprecipitation, phosphorylation assays, in vivo TNF-shock model, genetic KO Nature cell biology High 30420664
2019 TBK1 directly phosphorylates NDP52-associated ULK1 complex components; NDP52 recruits TBK1 to mitochondria/peroxisomes to focally activate the ULK1 complex, driving selective autophagosome biogenesis; this is independent of AMPK and mTOR. Chemically inducible dimerization (CID), CRISPR KO, live imaging Molecular cell High 30853401
2018 TBK1 directly phosphorylates RAB7A at Ser72 upon mitochondrial depolarization in a PARKIN-dependent manner, promoting FLCN-FNIP1 association and ATG9A vesicle recruitment to support mitophagy. Global quantitative proteomics, in vitro kinase assay, interaction proteomics with phosphomimetic/non-phosphorylatable mutants Science advances High 30627666
2019 TBK1 phosphorylates Syntaxin 17 (Stx17) at Ser202, translocating it from the Golgi to ATG13+FIP200+ pre-autophagosomal structures to control autophagy initiation; TBK1 or Stx17 knockout blocks ATG13 and FIP200 puncta formation. Phosphorylation site mapping, KO cell lines, live imaging, co-immunoprecipitation Developmental cell High 30827897
2018 TBK1 directly inhibits AMPK to repress cellular respiration and promote energy storage in adipocytes; conversely, AMPK activates TBK1 through ULK1-mediated phosphorylation under catabolic conditions. TBK1 also suppresses inflammation by phosphorylating and inducing degradation of NIK, attenuating NF-κB activity. Adipocyte-specific TBK1 KO mice, in vitro kinase assays, co-immunoprecipitation Cell High 29425491
2015 Loss-of-function mutations in TBK1 cause familial ALS; CCD2 domain mutations specifically disrupt TBK1 interaction with the adaptor protein optineurin, linking TBK1-optineurin interaction to ALS pathogenesis. Exome sequencing, in vitro co-immunoprecipitation, linkage analysis Nature neuroscience High 25803835
2017 TRIM23 undergoes K27-linked auto-ubiquitination of its ARF domain, which activates its GTP hydrolysis and facilitates TBK1 dimerization; activated TBK1 then phosphorylates p62 to promote selective autophagy. RNAi screen, ubiquitination assays, mechanistic mutagenesis, co-immunoprecipitation Nature microbiology High 28871090
2017 MAVS activates TBK1 and IKKε through TRAFs; TRAFs interact directly via their coiled-coil domain with the SDD domain of TBK1/IKKε, and TRAF E3 ligase activity synthesizes ubiquitin chains that activate NEMO and subsequently IKKα/β, which then phosphorylate TBK1/IKKε. Knockout cell lines, co-immunoprecipitation, epistasis analysis PLoS pathogens High 29125880
2015 TBK1 controls AKT-mTORC1 signaling in T cells by promoting AKT ubiquitination and degradation; T cell-specific TBK1 ablation causes enhanced T-cell activation and impaired effector T-cell egress from draining lymph nodes. T cell-conditional TBK1 KO mice, AKT ubiquitination assays, EAE model Nature communications High 25606824
2019 TBK1 is activated by growth factor signaling through a TBKBP1-CARD10-PKCθ axis; PKCθ phosphorylates TBK1 at Ser716, specifically enabling growth-factor-driven (not innate immune) TBK1 activation, which mediates mTORC1 activation and oncogenesis. Co-immunoprecipitation, phosphorylation site mutagenesis, conditional KO mice, lung cancer model Nature cell biology High 31792381
2017 TBK1 phosphorylates the exocyst subunit Exo84 upon RalA activation by insulin, reducing Exo84's affinity for RalA and enabling exocyst complex release to support GLUT4 vesicle fusion at the plasma membrane. In vitro kinase assay, KD/KO in adipocytes, phosphomimetic and non-phosphorylatable mutants, GLUT4 translocation assay Science signaling High 28325821
2020 TBK1 and IKKε act redundantly to mediate STING-induced NF-κB responses; TBK1 alone is dispensable for NF-κB activation but highly dependent upon for IRF3 activation downstream of cGAS-STING. Genetic KO (TBK1 and IKKε single and double KO), pharmacological inhibition, in vivo mouse studies Cell reports High 32268090
2021 TBK1 recruitment to STING via the STING C-terminal tail (not merely IRF3 binding) mediates autoinflammatory arthritis and NF-κB activation; STING S365A mutation (abrogating IRF3 binding) retains TBK1 recruitment and NF-κB activation causing arthritis, while STING L373A or C-terminal truncation disrupting TBK1 binding rescues DNase II-/- phenotypes. STING knock-in point mutant mice, in vivo disease model, cytokine neutralization The Journal of experimental medicine High 34901991
2020 TBK1 directly phosphorylates DRP1/DNM1L upon RLR-MAVS signaling activation, preventing DRP1 high-order oligomerization and mitochondrial fragmentation; this TBK1-DRP1 axis is essential for assembly of large MAVS aggregates and antiviral immunity. In vitro kinase assay, knock-in mouse models, dominant-negative mutant analysis, biochemical fractionation Molecular cell High 33171123
2021 TBK1 phosphorylates METTL3 at Ser67 upon viral infection; phospho-METTL3 associates with the translational complex to enhance protein translation of antiviral factors, and TBK1-mediated METTL3 activation stabilizes IRF3 mRNA via m6A modification. Phosphorylation site mapping, co-immunoprecipitation, KO mouse models Cell reports High 35172162
2021 PRMT1 directly interacts with TBK1 and catalyzes asymmetric dimethylation of TBK1 at R54, R134, and R228; this modification enhances TBK1 oligomerization after viral infection, promoting TBK1 phosphorylation and type I interferon production. In vitro methylation assay, co-immunoprecipitation, myeloid-specific KO mice, site-directed mutagenesis Cell reports High 34551290
2019 TBK1 activates TBK1 via a positive feedback mechanism at mitophagy contact sites; optineurin (OPTN) provides the platform by simultaneously binding ubiquitin and pre-autophagosomal structures, assembling the OPTN-TBK1 complex at mitochondria-autophagosome contact sites where hetero-autophosphorylation of TBK1 is initiated. Live imaging, CRISPR KO, engineered monobody inhibitors, biochemical fractionation The EMBO journal High 38287189
2020 TBC1D9 activates TBK1 during xenophagy and mitophagy in a Ca2+-dependent manner; TBC1D9's ubiquitin-binding region and Ca2+-binding motif mediate its association with ubiquitinated bacteria/mitochondria, and Ca2+ chelation impairs TBC1D9-ubiquitin interactions and blocks TBK1 activation. KO cell lines, co-immunoprecipitation, Ca2+ chelation experiments, xenophagy/mitophagy assays Nature communications High 32034138
2021 NEDD4 catalyzes K27-linked polyubiquitination of TBK1 at K344, which serves as a recognition signal for NDP52-mediated selective autophagic degradation of TBK1, thereby limiting type I IFN signaling. Ubiquitination assays with K344 mutagenesis, co-immunoprecipitation, selective autophagy assays Cell death and differentiation High 34257412
2017 The USP1-UAF1 deubiquitinase complex binds TBK1, removes K48-linked polyubiquitination, and stabilizes TBK1 protein levels, enhancing IRF3 activation and IFN-β production upon viral infection. Co-immunoprecipitation, ubiquitination assays, small molecule inhibitor (ML323), in vitro and in vivo viral infection The Journal of experimental medicine High 29138248
2020 TBK1 directly phosphorylates mTOR at S2159 within mTORC2, increasing mTORC2 intrinsic catalytic activity and downstream Akt phosphorylation; TBK1 co-immunoprecipitates with mTORC2. In vitro kinase assays, co-immunoprecipitation, Mtor S2159A knock-in mice, MEFs lacking TBK1 The Journal of biological chemistry High 34245780
2019 The receptor tyrosine kinase Axl induces TBK1 activity in a Ras-RalB-dependent manner in pancreatic cancer cells, driving epithelial-mesenchymal transition and metastasis. Loss-of-function studies (genetic and pharmacological), in vivo tumor models, pathway analysis JCI insight Medium 30938713
2021 TBK1 phosphorylates mutant huntingtin (mHTT) at S13 in vitro and in cells/in vivo, increasing mHTT exon1 phosphorylation, reducing its aggregation, and enhancing autophagic clearance to protect against toxicity in HD models. In vitro kinase assay coupled to MS, cell and primary neuron models, C. elegans experiments, site mapping The EMBO journal High 32757223
2019 TBK1 activates MVB12b by phosphorylation; this is essential for the sorting of bacterial DNA into extracellular vesicles enabling paracrine cGAS-STING signaling to bystander cells during Listeria infection. Phosphorylation assays, siRNA knockdown, extracellular vesicle isolation, bystander cell stimulation assays Nature microbiology Medium 30804548
2021 TBK1 interacts with NLRP3 and acts as an OFF switch limiting NLRP3 inflammasome activation; combined TBK1 and IKKε deletion (but not single KO) increases NLRP3 activation, and TBK1 controls NLRP3 at phospho-sites distinct from Ser3. Double KO (TBK1 and IKKε), pharmacological inhibition, mutagenesis, co-immunoprecipitation, in vivo peritonitis model Proceedings of the National Academy of Sciences of the United States of America High 34518217
2021 TBK1 is required for B cell germinal center formation by regulating the balance of IRF4/BCL6 expression through limiting CD40 and BCR activation via noncanonical NF-κB and AKT-T308 signaling. B cell-conditional TBK1 KO mice, immunization and malaria infection models, signaling assays The Journal of experimental medicine High 34910106
2022 TBK1 phosphorylates STING C-terminal tail at Ser366 and the phosphorylation requires TGN localization; after STING stimulation, TBK1 specifically associates with the trans-Golgi network (TGN), not other Golgi compartments, establishing TGN as the activation platform. Live-cell fluorescence imaging with stable fluorescent protein-tagged STING and TBK1, STING variant analysis Cell structure and function Medium 35125375
2019 NDP52 (CALCOCO2) forms a trimer with FIP200 (ULK complex) and SINTBAD/NAP1 (TBK1 complex) to recruit both kinase complexes to cargo, initiating selective autophagy at cargo-determined locations. Selective autophagy reconstitution, co-immunoprecipitation, CRISPR KO Autophagy Medium 31258038
2018 Loss of TBK1 kinase function protects against diet-induced metabolic dysfunction partly through loss of an inhibitory interaction between TBK1 and the insulin receptor. Global Tbk1 kinase-dead mutant mice, high-fat diet metabolic phenotyping, co-immunoprecipitation Molecular metabolism Medium 29935921
2024 TBK1 adaptors NAP1 and SINTBAD compete with OPTN for TBK1 binding, restricting mitophagy initiation, while simultaneously promoting NDP52-driven mitophagy by recruiting TBK1 to NDP52 and stabilizing NDP52-FIP200 interaction. Co-immunoprecipitation, CRISPR KO, selective autophagy assays, live imaging Nature structural & molecular biology High 38918639
2021 SIRT5 desuccinylates TBK1; succinylation at K38, K154, and K692 inhibits TBK1 binding to IRF3 and TRAF2 and suppresses inflammatory signaling; the K154/692R succinylation-resistant TBK1 mutant restores inflammatory cytokine production in macrophages. Succinylation site mutagenesis, adoptive macrophage transfer, in vivo sepsis model, co-immunoprecipitation Cell reports High 39673708
2025 SIRT5 desuccinylates TBK1 at lysine 137, leading to TBK1 dephosphorylation and suppression of downstream inflammatory pathways; SIRT5 deficiency increases TBK1 succinylation and hastens muscle cell senescence. SIRT5 KO in human myotubes, lentiviral gene therapy in mice, site-directed mutagenesis, co-immunoprecipitation Nature metabolism High 40087407
2023 PTK2B directly phosphorylates TBK1 at Tyr591, increasing TBK1 oligomerization and activation; PTK2B also promotes STING oligomerization in a kinase-independent manner; Ptk2b-deficient mice show increased susceptibility to viral infection. In vitro phosphorylation assay, co-immunoprecipitation, CRISPR KO, Ptk2b-deficient mice Nature communications High 37989995
2019 PINK1 and Parkin-mediated activation of TBK1 at mitochondria during mitophagy sequesters TBK1 from centrosomes, blocking its physiological role there and inhibiting mitosis; PINK1 and Parkin genetically interact with cell cycle regulators. Genetic interaction analysis, live imaging of TBK1 at mitochondria and centrosomes, PINK1/Parkin KO Cell reports Medium 31577952
2024 FIP200 controls TBK1 activation threshold at SQSTM1/p62-positive condensates; TBK1 is recruited to these condensates via TAX1BP1, phosphorylates SQSTM1/p62 at Ser403; loss of FIP200 or its inability to bind TAX1BP1 strongly increases TBK1 activation at condensates. Co-immunoprecipitation, KO cell lines, phosphorylation assays Scientific reports Medium 34226595
2022 Vimentin interacts with TBK1 and IKKε, disrupting TBK1-IRF3 and IKKε-IRF3 interactions, thereby inhibiting IRF3 phosphorylation and nuclear translocation and suppressing type I IFN production upon viral infection. Co-immunoprecipitation, overexpression and KO of vimentin, IFN reporter assays, vimentin KO mice Cell reports Medium 36223739
2022 TBK1 regulates YAP/TAZ activity in fibroblasts; TBK1 knockdown or inhibition reduces YAP/TAZ total and nuclear levels, suppressing fibrogenic activation; this is independent of LATS1/2 and IRF3 but dependent on proteasomal machinery. siRNA knockdown, pharmacological inhibition (MRT-68601), western blot, YAP/TAZ localization assays American journal of physiology. Lung cellular and molecular physiology Medium 32159970
2024 USP38 interacts with TBK1 and removes K48-linked polyubiquitination, stabilizing phospho-TBK1 and promoting its downstream signaling in pathological cardiac remodeling. Cardiac-specific USP38 KO and OE mice, co-immunoprecipitation, ubiquitination assays, TBK1 OE rescue International journal of biological sciences Medium 38481817
2018 ALS-associated TBK1 missense mutations (e.g., G217R) abolish TBK1 ability to phosphorylate IRF3 and optineurin, block binding to optineurin, and reduce homodimerization; this establishes loss of kinase function as a common mechanism for both missense and truncation ALS mutations. In vitro kinase assays, co-immunoprecipitation, patient-derived lymphoblastoid cell lines Neurobiology of aging High 30033073
2021 ALS-linked TBK1 mutations that abolish dimerization or kinase activity are individually insufficient to fully block mitophagy; mutations reducing both dimerization and kinase activity are more disruptive; TBK1 recruitment and OPTN phosphorylation at S177 are both necessary for autophagosomal engulfment of damaged mitochondria. Live imaging in cell lines and primary neurons, CRISPR KO, mitophagy flux assays Proceedings of the National Academy of Sciences of the United States of America High 34099552

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 2934 19847166
2003 IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nature immunology 2219 12692549
2012 STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Science signaling 1068 22394562
2019 Structural basis of STING binding with and phosphorylation by TBK1. Nature 849 30842653
2015 Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nature neuroscience 655 25803835
2019 Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective Autophagy. Molecular cell 389 30853401
2020 TBK1 and IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells. Cell reports 386 32268090
2018 TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging. Cell 377 30146158
2000 NAK is an IkappaB kinase-activating kinase. Nature 315 10783893
2017 TBK1: a new player in ALS linking autophagy and neuroinflammation. Molecular brain 241 28148298
2018 TBK1 and IKKε prevent TNF-induced cell death by RIPK1 phosphorylation. Nature cell biology 240 30420664
2018 TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue. Cell 232 29425491
2008 Are the IKKs and IKK-related kinases TBK1 and IKK-epsilon similarly activated? Trends in biochemical sciences 190 18353649
2017 TRIM23 mediates virus-induced autophagy via activation of TBK1. Nature microbiology 187 28871090
2013 Adenovirus detection by the cGAS/STING/TBK1 DNA sensing cascade. Journal of virology 186 24198409
2017 MAVS activates TBK1 and IKKε through TRAFs in NEMO dependent and independent manner. PLoS pathogens 175 29125880
2018 RAB7A phosphorylation by TBK1 promotes mitophagy via the PINK-PARKIN pathway. Science advances 174 30627666
2012 The pivotal role of TBK1 in inflammatory responses mediated by macrophages. Mediators of inflammation 149 23304064
2013 Negative regulation of TBK1-mediated antiviral immunity. FEBS letters 132 23395611
2011 TBK1 mediates crosstalk between the innate immune response and autophagy. Science signaling 132 21868362
2023 Targeting TBK1 to overcome resistance to cancer immunotherapy. Nature 127 36634707
2021 Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death. Cell 114 34363755
2019 Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation. Developmental cell 112 30827897
2019 Intracellular bacteria engage a STING-TBK1-MVB12b pathway to enable paracrine cGAS-STING signalling. Nature microbiology 107 30804548
2015 Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation. Nature communications 107 25606824
2022 The role of TBK1 in cancer pathogenesis and anticancer immunity. Journal of experimental & clinical cancer research : CR 105 35395857
2017 TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. Human mutation 89 28008748
2021 ALS- and FTD-associated missense mutations in TBK1 differentially disrupt mitophagy. Proceedings of the National Academy of Sciences of the United States of America 77 34099552
2016 Autophagy Inhibition Dysregulates TBK1 Signaling and Promotes Pancreatic Inflammation. Cancer immunology research 77 27068336
2020 TBK1, a central kinase in innate immune sensing of nucleic acids and beyond. Acta biochimica et biophysica Sinica 75 32458982
2019 Discovery of GSK8612, a Highly Selective and Potent TBK1 Inhibitor. ACS medicinal chemistry letters 75 31097999
2019 TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis. Nature cell biology 75 31792381
2019 PINK1/Parkin Influences Cell Cycle by Sequestering TBK1 at Damaged Mitochondria, Inhibiting Mitosis. Cell reports 74 31577952
2017 Association of Mutations in TBK1 With Sporadic and Familial Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. JAMA neurology 72 27892983
2018 ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function. Neurobiology of aging 70 30033073
2015 TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts. Neurobiology of aging 70 26476236
2023 Tiliroside targets TBK1 to induce ferroptosis and sensitize hepatocellular carcinoma to sorafenib. Phytomedicine : international journal of phytotherapy and phytopharmacology 69 36657316
2017 USP1-UAF1 deubiquitinase complex stabilizes TBK1 and enhances antiviral responses. The Journal of experimental medicine 69 29138248
2014 TBK1 gene duplication and normal-tension glaucoma. JAMA ophthalmology 69 24699864
2018 Roles for the IKK-Related Kinases TBK1 and IKKε in Cancer. Cells 66 30223576
2016 Therapeutic potential of targeting TBK1 in autoimmune diseases and interferonopathies. Pharmacological research 64 27353409
2015 Cutting Edge: Inhibiting TBK1 by Compound II Ameliorates Autoimmune Disease in Mice. Journal of immunology (Baltimore, Md. : 1950) 63 26432890
2021 TBK1 recruitment to STING mediates autoinflammatory arthritis caused by defective DNA clearance. The Journal of experimental medicine 57 34901991
2022 TBK1-METTL3 axis facilitates antiviral immunity. Cell reports 56 35172162
2020 TBK1-Mediated DRP1 Targeting Confers Nucleic Acid Sensing to Reprogram Mitochondrial Dynamics and Physiology. Molecular cell 56 33171123
2018 A single NaK channel conformation is not enough for non-selective ion conduction. Nature communications 50 29459730
2021 TBK1 and TNFRSF13B mutations and an autoinflammatory disease in a child with lethal COVID-19. NPJ genomic medicine 49 34210994
2016 Mutational analysis of TBK1 in Taiwanese patients with amyotrophic lateral sclerosis. Neurobiology of aging 49 26804609
2024 Optineurin provides a mitophagy contact site for TBK1 activation. The EMBO journal 45 38287189
2021 Selective autophagy controls the stability of TBK1 via NEDD4 to balance host defense. Cell death and differentiation 45 34257412
2020 TBC1D9 regulates TBK1 activation through Ca2+ signaling in selective autophagy. Nature communications 45 32034138
2020 Porcine Epidemic Diarrhea Virus nsp15 Antagonizes Interferon Signaling by RNA Degradation of TBK1 and IRF3. Viruses 44 32486349
2024 A TBK1-independent primordial function of STING in lysosomal biogenesis. Molecular cell 41 39423796
2019 Deletion of Tbk1 disrupts autophagy and reproduces behavioral and locomotor symptoms of FTD-ALS in mice. Aging 41 31039129
2020 Targeting TANK-binding kinase 1 (TBK1) in cancer. Expert opinion on therapeutic targets 40 32962465
2019 Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer. JCI insight 40 30938713
2021 The protein arginine methyltransferase PRMT1 promotes TBK1 activation through asymmetric arginine methylation. Cell reports 39 34551290
2020 TBK1 phosphorylates mutant Huntingtin and suppresses its aggregation and toxicity in Huntington's disease models. The EMBO journal 38 32757223
2015 Casein kinase II controls TBK1/IRF3 activation in IFN response against viral infection. Journal of immunology (Baltimore, Md. : 1950) 38 25810395
2018 Loss of Tbk1 kinase activity protects mice from diet-induced metabolic dysfunction. Molecular metabolism 37 29935921
2020 Discovery of BAY-985, a Highly Selective TBK1/IKKε Inhibitor. Journal of medicinal chemistry 36 31859507
2021 FIP200 controls the TBK1 activation threshold at SQSTM1/p62-positive condensates. Scientific reports 33 34226595
2020 TBK1 regulates YAP/TAZ and fibrogenic fibroblast activation. American journal of physiology. Lung cellular and molecular physiology 33 32159970
2022 TBK1-medicated DRP1 phosphorylation orchestrates mitochondrial dynamics and autophagy activation in osteoarthritis. Acta pharmacologica Sinica 31 36008706
2022 Vimentin inhibits type I interferon production by disrupting the TBK1-IKKε-IRF3 axis. Cell reports 31 36223739
2020 Dual TBK1/IKKε inhibitor amlexanox mitigates palmitic acid-induced hepatotoxicity and lipoapoptosis in vitro. Toxicology 31 32905826
2017 Phosphorylation of the exocyst protein Exo84 by TBK1 promotes insulin-stimulated GLUT4 trafficking. Science signaling 31 28325821
2024 Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD. Nature structural & molecular biology 30 38918639
2021 TBK1 interacts with tau and enhances neurodegeneration in tauopathy. The Journal of biological chemistry 30 33965374
2021 TANK-binding kinase 1 (TBK1): An emerging therapeutic target for drug discovery. Drug discovery today 30 34051368
2021 Peroxiredoxin 1 Interacts with TBK1/IKKε and Negatively Regulates Pseudorabies Virus Propagation by Promoting Innate Immunity. Journal of virology 30 34260286
2015 TANK-binding kinase 1 (TBK1) modulates inflammatory hyperalgesia by regulating MAP kinases and NF-κB dependent genes. Journal of neuroinflammation 30 25997745
2023 NLRC4 promotes the cGAS-STING signaling pathway by facilitating CBL-mediated K63-linked polyubiquitination of TBK1. Journal of medical virology 29 37537877
2021 TBK1 and IKKε act like an OFF switch to limit NLRP3 inflammasome pathway activation. Proceedings of the National Academy of Sciences of the United States of America 29 34518217
2022 Myeloid cell TBK1 restricts inflammatory responses. Proceedings of the National Academy of Sciences of the United States of America 28 35074921
2021 The cGAS/STING-TBK1-IRF Regulatory Axis Orchestrates a Primitive Interferon-Like Antiviral Mechanism in Oyster. Frontiers in immunology 28 34168656
2018 Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells. Scientific reports 28 30349097
2024 Enteric coronavirus nsp2 is a virulence determinant that recruits NBR1 for autophagic targeting of TBK1 to diminish the innate immune response. Autophagy 26 38597182
2017 TBK1 Promote Bladder Cancer Cell Proliferation and Migration via Akt Signaling. Journal of Cancer 24 28819387
2018 Zebrafish MVP Recruits and Degrades TBK1 To Suppress IFN Production. Journal of immunology (Baltimore, Md. : 1950) 23 30530482
2021 The innate immune kinase TBK1 directly increases mTORC2 activity and downstream signaling to Akt. The Journal of biological chemistry 22 34245780
2019 RNF144B inhibits LPS-induced inflammatory responses via binding TBK1. Journal of leukocyte biology 22 31509299
2015 Identification and further development of potent TBK1 inhibitors. ACS chemical biology 22 25540906
2022 Zebrafish MARCH8 downregulates fish IFN response by targeting MITA and TBK1 for protein degradation. Developmental and comparative immunology 21 35764162
2022 The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis. JCI insight 21 35917178
2018 SIKE of black carp is a substrate of TBK1 and suppresses TBK1-mediated antiviral signaling. Developmental and comparative immunology 21 30253130
2023 PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling. Nature communications 20 37989995
2019 CALCOCO2/NDP52 initiates selective autophagy through recruitment of ULK and TBK1 kinase complexes. Autophagy 20 31258038
2022 Specific association of TBK1 with the trans-Golgi network following STING stimulation. Cell structure and function 19 35125375
2017 Chicken TBK1 interacts with STING and is involved in IFN-β signaling regulation. Developmental and comparative immunology 19 28837824
2025 SIRT5 safeguards against primate skeletal muscle ageing via desuccinylation of TBK1. Nature metabolism 18 40087407
2024 Gasdermin B, an asthma-susceptibility gene, promotes MAVS-TBK1 signalling and airway inflammation. The European respiratory journal 18 38514093
2024 Emerging roles of TBK1 in cancer immunobiology. Trends in cancer 18 38519366
2020 Hemizygous deletion of Tbk1 worsens neuromuscular junction pathology in TDP-43G298S transgenic mice. Experimental neurology 18 33038415
2022 A co-crystal berberine-ibuprofen improves obesity by inhibiting the protein kinases TBK1 and IKKɛ. Communications biology 17 35962183
2021 B cell-intrinsic TBK1 is essential for germinal center formation during infection and vaccination in mice. The Journal of experimental medicine 17 34910106
2020 PGAM5-MAVS interaction regulates TBK1/ IRF3 dependent antiviral responses. Scientific reports 17 32433485
2019 Monocytes contribute to DNA sensing through the TBK1 signaling pathway in type 1 diabetes patients. Journal of autoimmunity 17 31256920
2024 Ubiquitin specific protease 38 aggravates pathological cardiac remodeling by stabilizing phospho-TBK1. International journal of biological sciences 16 38481817
2024 Desuccinylation of TBK1 by SIRT5 regulates inflammatory response of macrophages in sepsis. Cell reports 16 39673708