Affinage

TBK1

Serine/threonine-protein kinase TBK1 · UniProt Q9UHD2

Length
729 aa
Mass
83.6 kDa
Annotated
2026-06-10
100 papers in source corpus 52 papers cited in narrative 52 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TBK1 is a serine/threonine kinase that functions as a central signaling hub coupling innate immune sensing, selective autophagy, cell-death suppression, and metabolic control (PMID:12692549, PMID:30146158, PMID:29425491). In antiviral signaling, TBK1 is recruited to upstream scaffolds—STING via its C-terminal tail, and MAVS via TRAFs that engage the TBK1 SDD domain—whereupon it phosphorylates IRF3 to drive type I interferon induction, while STING-dependent NF-κB output is comparatively kinase-independent and redundant with IKKε (PMID:12692549, PMID:22394562, PMID:32268090, PMID:29125880, PMID:34901991). Cryo-EM of the cGAMP-STING–TBK1 complex established that substrate IRF3/STING phosphorylation requires trans-oligomerization, since the STING phosphosite cannot reach the active site of the TBK1 subunit that binds it (PMID:30842653). TBK1 enforces cell survival by directly phosphorylating RIPK1 within the TNFR1 complex—to which it is recruited through LUBAC-generated linear ubiquitin and the NEMO/TANK/NAP1 adaptors—to restrain RIPK1-driven apoptosis and necroptosis; this activity underlies the embryonic lethality of Tbk1 loss and human TBK1-deficiency autoinflammation (PMID:30146158, PMID:30420664, PMID:34363755). In selective autophagy, TBK1 is activated on cargo by adaptor platforms (optineurin, NDP52, TAX1BP1, with NAP1/SINTBAD tuning recruitment) and phosphorylates autophagy regulators including optineurin Ser177, p62/SQSTM1, Syntaxin 17 Ser202, and RAB7A Ser72 to control xenophagy, mitophagy, and autophagosome initiation (PMID:30627666, PMID:30853401, PMID:30827897, PMID:21868362, PMID:38918639). TBK1 additionally phosphorylates metabolic and mTOR-axis targets—AMPK, NIK, mTOR Ser2159, and Raptor Ser877—to govern energy homeostasis and growth signaling (PMID:29425491, PMID:31530866, PMID:34245780). Its activity is set by an extensive PTM code: activating arginine methylation by PRMT1 and tyrosine phosphorylation by PTK2B promote oligomerization and Ser172 autophosphorylation, whereas SIRT5-reversible succinylation and stabilizing/destabilizing ubiquitination further modulate the pool of active kinase (PMID:29138248, PMID:34257412, PMID:34551290, PMID:37989995, PMID:39673708). Genetically, TBK1 haploinsufficiency and kinase/dimerization-disrupting mutations cause familial ALS and frontotemporal dementia, in part by impairing optineurin binding and mitophagy (PMID:25803835, PMID:30033073, PMID:34099552).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 High

    Established TBK1 as an IKK-activating kinase, placing it upstream of NF-κB before its interferon role was known.

    Evidence In vitro kinase assay and dominant-negative overexpression with IκB degradation readout

    PMID:10783893

    Open questions at the time
    • Did not define physiological stimuli or scaffolds linking TBK1 to IKK in vivo
    • Direct vs indirect IKKβ phosphorylation under endogenous conditions not resolved
  2. 2003 High

    Identified the canonical antiviral function: TBK1 (with IKKε) phosphorylates IRF3 downstream of dsRNA sensing to induce type I interferon.

    Evidence Dominant-negative/siRNA knockdown with IRF3 phosphorylation and interferon reporter readouts

    PMID:12692549

    Open questions at the time
    • Upstream scaffold recruiting TBK1 to TLR3 not defined
    • Division of labor between TBK1 and IKKε left open
  3. 2009 High

    Revealed a non-immune survival role: TBK1 is selectively required by KRAS-mutant cancer cells through NF-κB anti-apoptotic signaling.

    Evidence Systematic RNAi screen with shRNA apoptosis follow-up across cell lines

    PMID:19847196

    Open questions at the time
    • Direct TBK1 substrates driving the survival signal not identified
    • Mechanism of selective dependence on mutant KRAS unresolved
  4. 2012 High

    Defined STING as the scaffold that physically couples TBK1 to its substrate IRF3, explaining substrate selection in cytosolic DNA sensing.

    Evidence In vitro reconstitution, mutagenesis, and co-immunoprecipitation separating TBK1 activation from IRF3 binding

    PMID:22394562

    Open questions at the time
    • Structural basis of activation not yet resolved
    • Whether STING also gates NF-κB output unaddressed
  5. 2015 High

    Connected TBK1 to human neurodegeneration, showing loss-of-function mutations cause ALS/FTD via haploinsufficiency and disrupted optineurin binding.

    Evidence Exome sequencing of ALS/FTD families with in vitro binding assays

    PMID:25803835

    Open questions at the time
    • Which TBK1 substrate(s) drive neurodegeneration not established
    • Cell-type-specific basis of motor neuron vulnerability unknown
  6. 2018 High

    Established the essential survival mechanism: TBK1 directly suppresses RIPK1 kinase to prevent apoptosis/inflammation, explaining Tbk1-null embryonic lethality.

    Evidence Genetic epistasis (Tbk1-/- × RIPK1 kinase-dead), TNFR1 complex Co-IP, and in vivo TNF shock models

    PMID:30146158 PMID:30420664

    Open questions at the time
    • RIPK1 phosphosite(s) targeted by TBK1 not fully mapped here
    • Relative contribution of IKKε in this complex left partial
  7. 2018 High

    Expanded TBK1 into metabolic and autophagy substrate space, identifying AMPK/NIK inhibition and direct RAB7A Ser72 phosphorylation for mitophagy.

    Evidence Conditional adipocyte KO mice, phosphoproteomics, in vitro kinase assays, and mitophagy imaging with phosphomutants

    PMID:29425491 PMID:30627666

    Open questions at the time
    • How TBK1 is targeted to specific metabolic vs autophagic substrates not unified
    • In vivo significance of RAB7A Ser72 for organismal mitophagy unresolved
  8. 2019 High

    Solved the activation mechanism structurally: STING tail insertion and the requirement for trans-oligomerization for substrate phosphorylation.

    Evidence Cryo-EM of cGAMP-STING–TBK1 complex with mutational validation

    PMID:30842653

    Open questions at the time
    • Structural basis for non-STING scaffold activation not addressed
    • How oligomerization is achieved at other organelles unclear
  9. 2019 High

    Defined TBK1's role in autophagy initiation through autophagy receptors and substrate phosphorylation (Stx17 Ser202, p62) that recruit the ULK1 machinery.

    Evidence Chemically inducible dimerization, CRISPR KO, in vitro kinase assays, and live-cell imaging

    PMID:28871090 PMID:30827897 PMID:30853401

    Open questions at the time
    • Hierarchy among multiple autophagy substrates not resolved
    • Whether all receptors use the same TBK1 activation route unclear
  10. 2019 High

    Mapped scaffold- and PTM-controlled activation modes distinguishing growth-factor from immune signaling, and linked TBK1 to mTOR and cancer phenotypes.

    Evidence Reciprocal Co-IP, phosphosite identification (TBK1 Ser716, Raptor Ser877), conditional KO tumor models, and VHL/PPM1B regulation

    PMID:30938713 PMID:31530866 PMID:31792381 PMID:31810986

    Open questions at the time
    • How distinct upstream adaptors select downstream substrate programs not integrated
    • Some axes (Axl-RalB, Raptor) rest on single-lab evidence
  11. 2020 High

    Separated IRF3 (kinase-dependent) from NF-κB (kinase-tolerant, IKKε-redundant) STING outputs and added DRP1/mitochondrial dynamics control.

    Evidence Single/double KO, pharmacological inhibition, in vivo validation, and DRP1 knock-in mimics with mitochondrial morphology assays

    PMID:32268090 PMID:33171123

    Open questions at the time
    • Kinase-independent NF-κB scaffolding function of TBK1 not mechanistically defined
    • How DRP1 phosphorylation integrates with antiviral MAVS aggregation in vivo unresolved
  12. 2021 High

    Resolved scaffold-encoded pathway choice in vivo and established that human TBK1 loss drives TNF/RIPK1-dependent autoinflammation treatable by anti-TNF.

    Evidence STING knock-in alleles with disease rescue in DNase II-/- mice; patient fibroblast necroptosis assays and anti-TNF treatment

    PMID:34363755 PMID:34901991

    Open questions at the time
    • Why human TBK1 loss tolerates interferon hypomorphism but not cell-death control not fully explained
    • Tissue-specific thresholds for autoinflammation unknown
  13. 2021 High

    Defined the optineurin-centered platform and PTM code (PRMT1 methylation) that drive TBK1 oligomerization and feedback autoactivation during mitophagy and interferon responses.

    Evidence Live-cell imaging, monobody inhibition, in vitro methylation with site mutagenesis, oligomerization assays, and myeloid Prmt1 KO mice

    PMID:34099552 PMID:34551290 PMID:38287189

    Open questions at the time
    • Quantitative interplay between activating and inhibitory PTMs not modeled
    • How ALS mutations perturb the OPTN feedback loop in neurons untested
  14. 2024 High

    Refined adaptor logic and organelle-localized pools controlling TBK1 substrate choice, including a lysosomal pool acting on Rab7–mTORC1 with disease-mutant consequences.

    Evidence Competitive binding/Co-IP for NAP1/SINTBAD vs OPTN, KO mitophagy assays, subcellular fractionation, and ALS-FTD mutant (E696K) analysis

    PMID:38918639 PMID:39103493

    Open questions at the time
    • General rules linking TBK1 subcellular localization to substrate selection not unified
    • How disease mutants shift the localization equilibrium in patient neurons unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the dense, partly antagonistic PTM and scaffold network is integrated to select among TBK1's many substrate programs in a given cell state remains unresolved.
  • No unified quantitative model of how methylation, succinylation, tyrosine phosphorylation, and ubiquitination jointly set TBK1 activity
  • Substrate prioritization across immune, autophagic, survival, and metabolic outputs not reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016740 transferase activity 7 GO:0098772 molecular function regulator activity 3
Localization
GO:0005739 mitochondrion 4 GO:0005829 cytosol 2 GO:0005764 lysosome 1 GO:0005783 endoplasmic reticulum 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-9612973 Autophagy 5 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1430728 Metabolism 2
Partners
IRF3MAVSNDP52OPTNRIPK1STING1TAX1BP1TBKBP1
Complex memberships
IKK complexTNFR1 signaling complex

Evidence

Reading pass · 52 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 NAK (TBK1) directly phosphorylates IKKβ in vitro to activate the IKK complex, leading to IκB degradation and NF-κB activation; endogenous NAK is activated by phorbol esters and growth factors, and catalytically inactive NAK specifically inhibits NF-κB activation by PKCε. In vitro kinase assay, dominant-negative overexpression, IκB degradation assay Nature High 10783893
2003 TBK1 and IKKε are essential components of the IRF3 signaling pathway downstream of TLR3 and viral dsRNA; both kinases phosphorylate IRF3 to drive type I interferon induction. Dominant-negative and siRNA knockdown, reporter assays, phosphorylation assays Nature immunology High 12692549
2009 TBK1 is selectively essential in KRAS-mutant cancer cells; TBK1 activates NF-κB anti-apoptotic signals involving c-Rel and BCL-XL that are required for survival in these cells. Systematic RNAi screen, shRNA knockdown with apoptosis readout, NF-κB pathway analysis Nature High 19847196
2012 STING functions as a scaffold protein that binds both TBK1 and IRF3; the C-terminal region of STING is necessary and sufficient to activate TBK1 and promote IRF3 phosphorylation; 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
2015 Loss-of-function mutations in TBK1 cause familial ALS and frontotemporal dementia via haploinsufficiency; C-terminal coiled-coil domain (CCD2) mutations disrupt TBK1 interaction with the adaptor protein optineurin. Exome sequencing of ALS/FTD patients, in vitro expression and binding assays, linkage analysis Nature neuroscience High 25803835
2018 TBK1 is an endogenous inhibitor of RIPK1 kinase; embryonic lethality of Tbk1-/- mice is rescued by inactivating RIPK1 kinase activity, establishing TBK1 as a suppressor of RIPK1-driven apoptosis and inflammation. Genetic epistasis (Tbk1-/- × RIPK1 kinase-dead mice), embryonic lethality rescue assay Cell High 30146158
2018 TBK1 and IKKε are recruited to the TNFR1 signaling complex via LUBAC-dependent linear ubiquitin; they phosphorylate RIPK1 in the TNFR1-SC to prevent TNF-induced cell death. NEMO mediates recruitment via adaptors TANK and NAP1. Co-immunoprecipitation of signaling complex, genetic knockout, in vivo TNF lethal shock model Nature cell biology High 30420664
2018 TBK1 directly phosphorylates RAB7A at Ser72 upon mitochondrial depolarization to promote mitophagy; this modification reduces RAB GDI association and increases FLCN-FNIP1 recruitment, and non-phosphorylatable RAB7A impairs mitophagy and ATG9A vesicle recruitment to damaged mitochondria. Quantitative phosphoproteomics, in vitro kinase assay, interaction proteomics with phosphomutants, mitophagy imaging Science advances High 30627666
2018 TBK1 directly inhibits AMPK to repress cellular respiration and increase energy storage in adipocytes; conversely, AMPK can increase TBK1 activity via its downstream target ULK1; TBK1 also suppresses inflammation by phosphorylating and inducing degradation of the IKK kinase NIK. Adipocyte-specific TBK1 knockout mice, in vitro kinase assays, phosphorylation and degradation assays Cell High 29425491
2019 Cryo-EM structure of TBK1 in complex with cGAMP-bound STING reveals that the STING C-terminal tail inserts as a β-strand into a groove between the TBK1 kinase domain and SDD of the second subunit; phosphorylation site Ser366 cannot reach the active site of bound TBK1, indicating that STING phosphorylation requires oligomerization of both proteins. Cryo-electron microscopy structure determination, mutational analysis Nature High 30842653
2019 NDP52 initiates selective autophagy by localizing and activating the ULK1 complex in a TBK1-dependent manner; ectopic placement of NDP52 on organelles is sufficient to induce selective autophagy; tethering ULK1 directly to cargo bypasses both autophagy receptors and TBK1 requirement. Chemically inducible dimerization (CID) assays, CRISPR KO lines, live-cell imaging Molecular cell High 30853401
2019 TBK1 phosphorylates Syntaxin 17 at Ser202; phospho-Stx17 translocates from the Golgi to ATG13+FIP200+ pre-autophagosomal structures to control autophagy initiation; TBK1 or Stx17 KO blocks ATG13/FIP200 puncta formation and reduces ULK1 complex assembly. Phosphorylation mapping, in vitro kinase assay, CRISPR KO, live-cell imaging, co-immunoprecipitation Developmental cell High 30827897
2019 TBK1 is activated by VHL loss or hypoxia in cancer cells; VHL-mediated hydroxylation of TBK1 at Pro48 promotes PPM1B phosphatase binding and TBK1 dephosphorylation; TBK1 phosphorylates p62/SQSTM1 at Ser366, which is essential for p62 stability and cancer cell proliferation. Genetic ablation, pharmacological inhibition, PROTAC degradation, phosphorylation assays, xenograft model Cancer discovery High 31810986
2019 TBKBP1 recruits TBK1 to PKCθ via scaffold protein CARD10; PKCθ phosphorylates TBK1 at Ser716, a step required for TBK1 activation by growth factors but not innate immune stimuli; the TBK1-TBKBP1 axis mediates mTORC1 activation, oncogenesis, and PD-L1 induction. Co-immunoprecipitation, phosphorylation assays, conditional knockout mice, lung cancer model Nature cell biology High 31792381
2019 PINK1/Parkin-mediated TBK1 activation at damaged mitochondria during mitophagy sequesters TBK1 from its physiological role at centrosomes, causing a block in mitosis. Genetic interaction screen, live-cell imaging, mitosis assays Cell reports Medium 31577952
2019 Axl receptor tyrosine kinase induces TBK1 activity through a Ras-RalB-dependent mechanism to drive epithelial-mesenchymal transition in KRAS-mutant pancreatic cancer. Genetic knockdown, pharmacological inhibition, EMT marker analysis, invasion/metastasis assays JCI insight Medium 30938713
2019 TBK1 promotes Raptor Ser877 phosphorylation in vitro and in cells; this modification limits mTORC1 activity, as a non-phosphorylatable Raptor S877A mutant increases mTORC1 signaling. In vitro kinase assay coupled with mass spectrometry, phosphosite mutagenesis, mTORC1 activity assays Scientific reports Medium 31530866
2020 TBK1 is redundant with IKKε for STING-induced NF-κB responses in myeloid cells; IRF3 activation is highly dependent on TBK1 kinase activity, whereas NF-κB is significantly less sensitive to TBK1/IKKε kinase inhibition. Genetic KO (single and double), pharmacological inhibition, reporter assays, in vivo validation Cell reports High 32268090
2020 TBK1 directly phosphorylates DRP1/DNM1L upon RLR-MAVS signaling activation; this phosphorylation prevents DRP1 oligomerization and mitochondrial fragmentation, and is required for assembly of large MAVS aggregates and efficient antiviral immunity. In vitro kinase assay, knockin (KI) strategy mimicking TBK1-DRP1 signaling, co-immunoprecipitation, mitochondrial morphology assays Molecular cell High 33171123
2020 TBK1 directly interacts with mTORC2 and phosphorylates mTOR at Ser2159 within mTORC2; this increases mTORC2 intrinsic catalytic activity and Akt phosphorylation; TBK1-mTOR S2159 phosphorylation also promotes mTORC1 signaling. Co-immunoprecipitation of mTORC2, in vitro kinase assay, Mtor S2159A knock-in MEFs and mice The Journal of biological chemistry High 34245780
2017 TBK1 directly phosphorylates the autophagy adaptor optineurin (OPTN) at Ser177 after Salmonella invasion, enhancing OPTN interaction with Atg8 family proteins and recruiting the autophagic machinery to intracellular bacteria for xenophagy. In vitro kinase assay, co-immunoprecipitation, bacterial clearance assays Science signaling (review citing primary data); primary mechanism originally described 2011 High 21868362
2017 TRIM23 undergoes K27-linked auto-ubiquitination on its ARF domain, enabling GTP hydrolysis activity and facilitating TBK1 dimerization; active TBK1 then phosphorylates p62 to promote selective autophagy. RNAi screen, mutagenesis of ubiquitination sites, TBK1 dimerization assay, p62 phosphorylation assay Nature microbiology High 28871090
2017 MAVS recruits TBK1/IKKε via TRAFs; TRAFs interact directly with the SDD domain of TBK1/IKKε via their coiled-coil domain; TRAF E3 ligase activity synthesizes ubiquitin chains to activate NEMO; NEMO-activated IKKα/β then further phosphorylate and activate TBK1/IKKε. TRAF quadruple knockout cells, co-immunoprecipitation, ubiquitination assays, domain mapping PLoS pathogens High 29125880
2017 USP1-UAF1 deubiquitinase complex binds TBK1, removes K48-linked polyubiquitination, and prevents TBK1 proteasomal degradation, thereby stabilizing TBK1 and enhancing antiviral IFN responses. Co-immunoprecipitation, ubiquitination assays, USP1-UAF1 inhibitor ML323, in vitro and in vivo viral infection The Journal of experimental medicine Medium 29138248
2015 TBK1 controls AKT ubiquitination and degradation to regulate T-cell activation and migration; T-cell-specific TBK1 ablation deregulates AKT-mTORC1 signaling, enhancing T-cell activation and impairing effector T-cell egress from draining lymph nodes. T-cell-conditional TBK1 knockout mice, AKT ubiquitination assay, mTORC1 activity assays, EAE model Nature communications Medium 25606824
2021 TBK1 is recruited to STING via the STING C-terminal tail; STING S365A mutation (abolishing IRF3 binding) allows TBK1 recruitment and NF-κB activation but not IRF3 activation; disruption of TBK1 binding to STING (L373A or C-terminal truncation) prevents both pathways and rescues autoinflammatory disease in DNase II-/- mice. Genetic knockin mice (STING S365A, L373A, C-terminal truncation), disease rescue experiments in DNase II-/- mice, cytokine neutralization The Journal of experimental medicine High 34901991
2021 TBK1 loss in humans causes autoinflammation driven by TNF-induced RIPK1-dependent cell death (necroptosis); patient-derived fibroblasts with homozygous TBK1 loss show elevated necroptosis in vitro; IFN-I induction via RIG-I/MDA5 is hypomorphic but sufficient in the absence of TBK1. Patient-derived fibroblasts, necroptosis assays, ex vivo cytokine profiling, anti-TNF treatment Cell High 34363755
2021 TBK1 phosphorylates full-length and N-terminal huntingtin at Ser13/Ser16 in vitro and at Ser13 in cells and in vivo; TBK1-mediated phosphorylation inhibits mutant HTT aggregation and increases autophagic clearance, reducing cytotoxicity. In vitro kinase assay, cell-based phosphorylation assay, aggregation assays, autophagy flux assay, C. elegans model The EMBO journal High 32757223
2021 TBK1 interacts with tau in human AD brain tissue and phosphorylates tau in vitro at multiple sites; TBK1 activation in Drosophila tauopathy model triggers tau hyperphosphorylation and enhanced neurodegeneration, while TBK1 ortholog knockdown suppresses tau toxicity. Immunoaffinity enrichment + mass spectrometry from human brain, in vitro kinase assay + MS, Drosophila genetic epistasis The Journal of biological chemistry Medium 33965374
2021 NEDD4 E3 ligase catalyzes K27-linked polyubiquitination of TBK1 at K344, targeting TBK1 for NDP52-mediated selective autophagic degradation; this limits TBK1 protein levels at late stages of viral infection to prevent excessive immune response. Ubiquitination assays (K27 linkage), co-immunoprecipitation, autophagy flux assays, viral infection Cell death and differentiation Medium 34257412
2021 PRMT1 directly interacts with TBK1 and catalyzes asymmetric arginine methylation at R54, R134, and R228; this modification enhances TBK1 oligomerization and subsequent Ser172 autophosphorylation and downstream type I IFN production. Co-immunoprecipitation, in vitro methylation assay, site-directed mutagenesis, oligomerization assay, myeloid-specific Prmt1 KO mice Cell reports High 34551290
2021 TBK1 interacts with NLRP3 and acts as a phospho-switch to limit NLRP3 inflammasome activation; TBK1 and IKKε together constitute an OFF switch for NLRP3 via phosphorylation at a site distinct from Ser3; simultaneous deletion of both kinases is required to fully release NLRP3 activation. Single and double KO macrophages, pharmacological inhibition, NLRP3 mutagenesis, co-immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America Medium 34518217
2022 TBK1 phosphorylates METTL3 at Ser67 upon viral infection; phospho-METTL3 interacts with the translational complex to enhance protein translation and m6A modification, stabilizing IRF3 mRNA to facilitate antiviral responses. Co-immunoprecipitation, phosphorylation mapping, METTL3 KO cells and Mettl3 conditional KO mice, viral infection models Cell reports Medium 35172162
2020 TBC1D9, a Ca2+-binding protein, mediates TBK1 activation during xenophagy and mitophagy; upon bacterial infection, Ca2+ increase promotes TBC1D9 binding to ubiquitin-coated bacteria via its UBR and Ca2+-binding motif, and TBC1D9 KO suppresses TBK1 activation and ULK1 complex recruitment. Co-immunoprecipitation, TBC1D9 knockout cells, Ca2+ chelation experiments, live-cell imaging Nature communications Medium 32034138
2011 TBK1 controls an antiapoptotic response downstream of TNF by triggering a specific RelA/p65 phosphorylation event, resulting in PAI-2 expression; PAI-2 limits caspase-3 activation by stabilizing transglutaminase 2, which cross-links and inactivates procaspase-3. Genetic studies in Tg2-/- mice, RelA phosphorylation mapping, caspase-3 activation assay, TNF liver injury models Proceedings of the National Academy of Sciences of the United States of America Medium 22203995
2011 IKKε/TBK1 activate Pellino 1 in vitro by phosphorylating Ser76, Thr288, and Ser293, converting it into an active E3 ubiquitin ligase; endogenous Pellino 1 E3 ligase activity is activated in LPS/poly(I:C)-stimulated macrophages in a TBK1/IKKε-dependent manner. In vitro kinase assay, two-hybrid screen, E3 ligase activity assay, IKKε/TBK1 pharmacological inhibition in macrophages The Biochemical journal Medium 21204785
2018 ALS-associated TBK1 missense mutations (G217R, R357X) abolish TBK1 ability to phosphorylate IRF3 and optineurin, impair TBK1 homodimerization (G217R), and reduce optineurin binding; proportion of active (phosphorylated) TBK1 is reduced in lymphoblastoid cell lines from mutation carriers. In vitro kinase assay with IRF3 and OPTN substrates, dimerization assay, patient-derived cell lines Neurobiology of aging Medium 30033073
2021 Optineurin provides a unique platform for TBK1 activation at mitophagy contact sites between damaged mitochondria and autophagosome formation sites; both OPTN-ubiquitin and OPTN-PAS interaction axes facilitate OPTN-TBK1 complex assembly, initiating a positive feedback loop of TBK1 hetero-autophosphorylation. Live-cell imaging, engineered monobodies blocking OPTN, Co-IP, mitophagy flux assays The EMBO journal High 38287189
2021 ALS-linked TBK1 mutations that abolish both dimerization and kinase activity are most disruptive to mitophagy; TBK1 recruitment and OPTN phosphorylation at S177 are each necessary for engulfment of damaged mitochondria; ULK1 activity also contributes to OPTN S177 phosphorylation. Quantitative imaging of mitophagy in cells expressing ALS mutants, kinase assays, ULK1 inhibition Proceedings of the National Academy of Sciences of the United States of America Medium 34099552
2024 NAP1 and SINTBAD, two TBK1 adaptors, restrict OPTN-driven mitophagy initiation by competing with OPTN for TBK1 binding; they promote NDP52-driven mitophagy progression by recruiting TBK1 to NDP52 and stabilizing its interaction with FIP200; OPTN is the primary recruiter of TBK1 during mitophagy initiation. Co-immunoprecipitation, competitive binding assays, knockout cells, mitophagy flux assays Nature structural & molecular biology High 38918639
2024 A lysosome-localized pool of TBK1 is recruited upon elevated amino acid levels and phosphorylates Rab7 at Ser72 to relieve Rab7-dependent inhibition of mTORC1; an ALS-FTD-associated TBK1 mutant (E696K) constitutively accumulates at lysosomes, causing elevated Rab7 phosphorylation and increased mTORC1 activation. Subcellular fractionation, co-immunoprecipitation, phosphorylation assays, mTORC1 activity assays, disease mutant analysis The EMBO journal High 39103493
2024 FIP200 controls the TBK1 activation threshold at SQSTM1/p62-positive condensates; TBK1 is recruited to p62 aggregates via TAX1BP1 and phosphorylates p62 at Ser403; removal of FIP200 or disruption of FIP200-TAX1BP1 interaction strongly increases TBK1 activation at these condensates. Co-immunoprecipitation, phosphorylation assays, FIP200 KO cells, aggregate imaging Scientific reports (2021) Medium 34226595
2023 PTK2B directly phosphorylates TBK1 at Tyr591 to increase TBK1 oligomerization and activation; PTK2B also promotes STING oligomerization in a kinase-independent manner; Ptk2b-deficient mice are more susceptible to viral infection. Co-immunoprecipitation, in vitro kinase assay, mutagenesis of Tyr591, Ptk2b KO mice, viral infection Nature communications Medium 37989995
2024 SIRT5 desuccinylates TBK1 at Lys137, leading to TBK1 dephosphorylation and suppression of downstream inflammatory signaling; reduced SIRT5 in aged primate skeletal muscle increases TBK1 succinylation and promotes inflammation. In vitro succinylation/desuccinylation assays, site mutagenesis (K137), SIRT5 KO/overexpression in myotubes, primate muscle tissue analysis Nature metabolism Medium 40087407
2024 SIRT5 desuccinylates TBK1 at K38, K154, and K692 in macrophages; succinylation at these sites inhibits TBK1 binding to IRF3 and TRAF2, suppressing inflammatory signaling; macrophage adoptive transfer of succinylation-resistant TBK1-2KR (K154/692R) exacerbates sepsis-induced lung injury. Succinylation site mapping, mutagenesis, Co-IP, macrophage adoptive transfer, sepsis model Cell reports Medium 39673708
2021 Myeloid cell TBK1 suppresses NF-κB and MAP kinase signaling pathways in macrophages to attenuate induction of proinflammatory cytokines, particularly IL-1β; myeloid-specific TBK1 KO causes spontaneous adipose inflammation and exacerbates colitis, and IL-1R1 ablation eliminates these inflammatory symptoms. Myeloid-conditional TBK1 KO mice, NF-κB/MAPK signaling assays, cytokine measurements, IL-1R1 double KO Proceedings of the National Academy of Sciences of the United States of America Medium 35074921
2024 CDK4/6 phosphorylates TBK1 at Ser527 to inactivate STING signaling in prostate cancer; CDK4/6-mediated phosphorylation of RB1 at Ser249/Thr252 also induces RB1-TBK1 interaction, reducing TBK1 Ser172 phosphorylation and suppressing the STING pathway. Phosphorylation assays, Co-immunoprecipitation, CDK4/6 inhibitor treatment, prostate cancer cell models Cancer research Medium 38861362
2023 Tiliroside directly binds TBK1 (confirmed by molecular docking and biolayer interferometry) and inhibits its enzymatic activity, reducing p62 Ser349 phosphorylation and Keap1-Nrf2 axis activity to induce ferroptosis in hepatocellular carcinoma cells. Biolayer interferometry binding assay, enzymatic activity assay, Co-IP, xenograft tumor models Phytomedicine Medium 36657316
2023 NLRC4 facilitates the interaction between TBK1 and the E3 ubiquitin ligase CBL to enhance K63-linked polyubiquitination of TBK1, promoting cGAS-STING pathway activation and TBK1 phosphorylation. Co-immunoprecipitation, ubiquitination assays (K63-specific), NLRC4 KO cells and Nlrc4-/- mice, viral infection Journal of medical virology Medium 37537877
2021 Loss of TBK1 kinase function protects against diet-induced metabolic dysfunction through loss of an inhibitory interaction between TBK1 and the insulin receptor. Global Tbk1 kinase-dead mutant mice, metabolic profiling, insulin receptor interaction assay Molecular metabolism Medium 29935921
2022 The MAM-specific E3 ubiquitin ligase AMFR ubiquitinates nascent proteins at the MAM to activate TBK1; TBK1 activation at the MAM results in ribosomal protein degradation under proteostatic stress; MAM or TBK1 deficiency impairs this response and increases cellular vulnerability. MAM fractionation, TBK1 KO, AMFR knockdown, ribosomal degradation assay, in vitro and in vivo models Proceedings of the National Academy of Sciences of the United States of America Medium 37967220
2020 Vimentin interacts with TBK1 and IKKε to disrupt TBK1-IRF3 and IKKε-IRF3 interactions, inhibiting IRF3 phosphorylation and nuclear translocation and suppressing type I IFN production. Co-immunoprecipitation, vimentin KO mice, overexpression, IRF3 localization assay Cell reports (2022) Medium 36223739

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 2994 19847166
2003 IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nature immunology 2227 12692549
2012 STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Science signaling 1092 22394562
2019 Structural basis of STING binding with and phosphorylation by TBK1. Nature 878 30842653
2015 Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nature neuroscience 659 25803835
2020 TBK1 and IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells. Cell reports 399 32268090
2019 Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective Autophagy. Molecular cell 394 30853401
2018 TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging. Cell 382 30146158
2000 NAK is an IkappaB kinase-activating kinase. Nature 316 10783893
2018 TBK1 and IKKε prevent TNF-induced cell death by RIPK1 phosphorylation. Nature cell biology 245 30420664
2017 TBK1: a new player in ALS linking autophagy and neuroinflammation. Molecular brain 243 28148298
2018 TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue. Cell 235 29425491
2017 TRIM23 mediates virus-induced autophagy via activation of TBK1. Nature microbiology 190 28871090
2008 Are the IKKs and IKK-related kinases TBK1 and IKK-epsilon similarly activated? Trends in biochemical sciences 190 18353649
2017 MAVS activates TBK1 and IKKε through TRAFs in NEMO dependent and independent manner. PLoS pathogens 181 29125880
2018 RAB7A phosphorylation by TBK1 promotes mitophagy via the PINK-PARKIN pathway. Science advances 180 30627666
2016 Human TBK1: A Gatekeeper of Neuroinflammation. Trends in molecular medicine 171 27211305
2012 The pivotal role of TBK1 in inflammatory responses mediated by macrophages. Mediators of inflammation 149 23304064
2023 Targeting TBK1 to overcome resistance to cancer immunotherapy. Nature 133 36634707
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
2021 Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death. Cell 115 34363755
2019 Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation. Developmental cell 115 30827897
2022 The role of TBK1 in cancer pathogenesis and anticancer immunity. Journal of experimental & clinical cancer research : CR 113 35395857
2015 Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation. Nature communications 107 25606824
2019 TBK1 Is a Synthetic Lethal Target in Cancer with VHL Loss. Cancer discovery 94 31810986
2020 TBK1, a central kinase in innate immune sensing of nucleic acids and beyond. Acta biochimica et biophysica Sinica 80 32458982
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 79 34099552
2019 TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis. Nature cell biology 77 31792381
2016 Autophagy Inhibition Dysregulates TBK1 Signaling and Promotes Pancreatic Inflammation. Cancer immunology research 77 27068336
2019 PINK1/Parkin Influences Cell Cycle by Sequestering TBK1 at Damaged Mitochondria, Inhibiting Mitosis. Cell reports 75 31577952
2023 Tiliroside targets TBK1 to induce ferroptosis and sensitize hepatocellular carcinoma to sorafenib. Phytomedicine : international journal of phytotherapy and phytopharmacology 72 36657316
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
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 67 30223576
2016 Therapeutic potential of targeting TBK1 in autoimmune diseases and interferonopathies. Pharmacological research 64 27353409
2021 TBK1 recruitment to STING mediates autoinflammatory arthritis caused by defective DNA clearance. The Journal of experimental medicine 61 34901991
2022 TBK1-METTL3 axis facilitates antiviral immunity. Cell reports 59 35172162
2011 TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2. Proceedings of the National Academy of Sciences of the United States of America 59 22203995
2020 TBK1-Mediated DRP1 Targeting Confers Nucleic Acid Sensing to Reprogram Mitochondrial Dynamics and Physiology. Molecular cell 57 33171123
2021 TBK1 and TNFRSF13B mutations and an autoinflammatory disease in a child with lethal COVID-19. NPJ genomic medicine 49 34210994
2011 The role of TBK1 and IKKε in the expression and activation of Pellino 1. The Biochemical journal 49 21204785
2024 Optineurin provides a mitophagy contact site for TBK1 activation. The EMBO journal 48 38287189
2024 A TBK1-independent primordial function of STING in lysosomal biogenesis. Molecular cell 48 39423796
2021 Selective autophagy controls the stability of TBK1 via NEDD4 to balance host defense. Cell death and differentiation 46 34257412
2020 TBC1D9 regulates TBK1 activation through Ca2+ signaling in selective autophagy. Nature communications 45 32034138
2020 Targeting TANK-binding kinase 1 (TBK1) in cancer. Expert opinion on therapeutic targets 43 32962465
2019 Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer. JCI insight 43 30938713
2015 TBK1 inhibitors: a review of patent literature (2011 - 2014). Expert opinion on therapeutic patents 43 26293650
2019 Deletion of Tbk1 disrupts autophagy and reproduces behavioral and locomotor symptoms of FTD-ALS in mice. Aging 41 31039129
2021 The protein arginine methyltransferase PRMT1 promotes TBK1 activation through asymmetric arginine methylation. Cell reports 40 34551290
2020 TBK1 phosphorylates mutant Huntingtin and suppresses its aggregation and toxicity in Huntington's disease models. The EMBO journal 38 32757223
2018 Loss of Tbk1 kinase activity protects mice from diet-induced metabolic dysfunction. Molecular metabolism 37 29935921
2021 FIP200 controls the TBK1 activation threshold at SQSTM1/p62-positive condensates. Scientific reports 36 34226595
2019 TBK1 Limits mTORC1 by Promoting Phosphorylation of Raptor Ser877. Scientific reports 36 31530866
2024 Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD. Nature structural & molecular biology 34 38918639
2020 TBK1 regulates YAP/TAZ and fibrogenic fibroblast activation. American journal of physiology. Lung cellular and molecular physiology 34 32159970
2022 Vimentin inhibits type I interferon production by disrupting the TBK1-IKKε-IRF3 axis. Cell reports 33 36223739
2021 TANK-binding kinase 1 (TBK1): An emerging therapeutic target for drug discovery. Drug discovery today 32 34051368
2020 Dual TBK1/IKKε inhibitor amlexanox mitigates palmitic acid-induced hepatotoxicity and lipoapoptosis in vitro. Toxicology 32 32905826
2023 NLRC4 promotes the cGAS-STING signaling pathway by facilitating CBL-mediated K63-linked polyubiquitination of TBK1. Journal of medical virology 31 37537877
2022 TBK1-medicated DRP1 phosphorylation orchestrates mitochondrial dynamics and autophagy activation in osteoarthritis. Acta pharmacologica Sinica 31 36008706
2021 TBK1 interacts with tau and enhances neurodegeneration in tauopathy. The Journal of biological chemistry 31 33965374
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 30 34518217
2020 FXYD protein isoforms differentially modulate human Na/K pump function. The Journal of general physiology 30 33231612
2022 Myeloid cell TBK1 restricts inflammatory responses. Proceedings of the National Academy of Sciences of the United States of America 29 35074921
2024 Enteric coronavirus nsp2 is a virulence determinant that recruits NBR1 for autophagic targeting of TBK1 to diminish the innate immune response. Autophagy 28 38597182
2018 Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells. Scientific reports 28 30349097
2017 TBK1 Promote Bladder Cancer Cell Proliferation and Migration via Akt Signaling. Journal of Cancer 24 28819387
2016 Tank-Binding Kinase 1 (TBK1) Gene and Open-Angle Glaucomas (An American Ophthalmological Society Thesis). Transactions of the American Ophthalmological Society 24 27881886
2025 SIRT5 safeguards against primate skeletal muscle ageing via desuccinylation of TBK1. Nature metabolism 23 40087407
2022 The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis. JCI insight 23 35917178
2021 The innate immune kinase TBK1 directly increases mTORC2 activity and downstream signaling to Akt. The Journal of biological chemistry 23 34245780
2018 Zebrafish MVP Recruits and Degrades TBK1 To Suppress IFN Production. Journal of immunology (Baltimore, Md. : 1950) 23 30530482
2015 Identification and further development of potent TBK1 inhibitors. ACS chemical biology 23 25540906
2024 Desuccinylation of TBK1 by SIRT5 regulates inflammatory response of macrophages in sepsis. Cell reports 22 39673708
2019 Myeloid TBK1 Signaling Contributes to the Immune Response to Influenza. American journal of respiratory cell and molecular biology 22 30290124
2024 Emerging roles of TBK1 in cancer immunobiology. Trends in cancer 21 38519366
2022 Zebrafish MARCH8 downregulates fish IFN response by targeting MITA and TBK1 for protein degradation. Developmental and comparative immunology 21 35764162
2023 PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling. Nature communications 20 37989995
2024 Ubiquitin specific protease 38 aggravates pathological cardiac remodeling by stabilizing phospho-TBK1. International journal of biological sciences 19 38481817
2024 Gasdermin B, an asthma-susceptibility gene, promotes MAVS-TBK1 signalling and airway inflammation. The European respiratory journal 19 38514093
2020 PGAM5-MAVS interaction regulates TBK1/ IRF3 dependent antiviral responses. Scientific reports 19 32433485
2017 Chicken TBK1 interacts with STING and is involved in IFN-β signaling regulation. Developmental and comparative immunology 19 28837824
2016 Regulation of TBK1 activity by Optineurin contributes to cell cycle-dependent expression of the interferon pathway. Cytokine & growth factor reviews 19 26976762
2020 Hemizygous deletion of Tbk1 worsens neuromuscular junction pathology in TDP-43G298S transgenic mice. Experimental neurology 18 33038415
2024 CDK4/6 Alters TBK1 Phosphorylation to Inhibit the STING Signaling Pathway in Prostate Cancer. Cancer research 17 38861362
2023 Tetrandrine alleviates atherosclerosis via inhibition of STING-TBK1 pathway and inflammation in macrophages. International immunopharmacology 17 37099944
2022 A co-crystal berberine-ibuprofen improves obesity by inhibiting the protein kinases TBK1 and IKKɛ. Communications biology 17 35962183
2020 Inhibition of TBK1 by amlexanox attenuates paraquat-induced acute lung injury. Toxicology 17 32763286
2019 Monocytes contribute to DNA sensing through the TBK1 signaling pathway in type 1 diabetes patients. Journal of autoimmunity 17 31256920
2023 TBK1 promotes thyroid cancer progress by activating the PI3K/Akt/mTOR signaling pathway. Immunity, inflammation and disease 16 36988258
2023 Mitochondria-associated membrane collapse impairs TBK1-mediated proteostatic stress response in ALS. Proceedings of the National Academy of Sciences of the United States of America 16 37967220
2022 TBK1-mTOR Signaling Attenuates Obesity-Linked Hyperglycemia and Insulin Resistance. Diabetes 16 35983955
2022 TRIM27 is an autophagy substrate facilitating mitochondria clustering and mitophagy via phosphorylated TBK1. The FEBS journal 16 36111389
1990 Ionic regulation of the biosynthesis of NaK-ATPase subunits. Seminars in nephrology 16 2166328
2024 Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition. The EMBO journal 15 39103493

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