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TANK-binding kinase 1

TANK-binding kinase 1 (TBK1) is a serine/threonine protein kinase encoded by the TBK1 gene on human chromosome 12q14.2, playing a central role in innate immune signaling by integrating pathogen recognition receptor (PRR) inputs to activate transcription factors such as NF-κB and IRF3, thereby inducing type I interferon production and inflammatory responses to viral and bacterial threats.^[1]^[2] As a non-canonical IκB kinase family member, TBK1 is ubiquitously expressed across human tissues, with particularly high levels in testis and bone marrow, and it functions through autophosphorylation and dimerization to propagate signals from pathways including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and the cGAS-STING axis.^[1]^[3]^[4] Beyond immunity, TBK1 regulates diverse cellular processes such as autophagy, mitophagy, and cell survival, where it phosphorylates substrates like optineurin and p62 to promote selective degradation of damaged organelles and pathogens.^[3] In cancer, TBK1 exhibits dual roles: it drives tumor cell proliferation and survival via RAS/ERK and AKT signaling in oncogene-addicted malignancies like KRAS-mutant lung cancer, yet it also enhances antitumor immunity by promoting cytokine production in dendritic cells and macrophages.^[5]^[6] Structurally, TBK1 features an N-terminal kinase domain, a central ubiquitin-like domain, and a C-terminal scaffold/dimerization domain, enabling its activation through K63-linked ubiquitination and interactions with adaptors like TANK and NAP1.^[7]^[4] Dysregulation of TBK1 is implicated in neurodegenerative diseases, with heterozygous loss-of-function mutations causing amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), often through haploinsufficiency leading to neuroinflammation and protein aggregation.^[1]^[2] Additionally, TBK1 hyperactivity contributes to chronic inflammatory conditions and has emerged as a therapeutic target, with inhibitors like BX795 and MRT67307 showing promise in blocking tumor evasion of immune surveillance and mitigating autoinflammatory responses.^[5]^[6]

Gene and Expression

Gene Location and Organization

The TBK1 gene is located on the long arm of human chromosome 12 at the q14.2 cytogenetic band, with genomic coordinates spanning from 64,452,120 to 64,502,114 in the GRCh38.p14 assembly, encompassing approximately 50 kb of DNA.^[1] This positioning places TBK1 within a region associated with various neurological disorders, though the gene itself spans a compact genomic interval relative to its functional importance.^[8] The gene structure comprises 22 exons, which encode the primary transcript and support alternative splicing events.^[1] Regulatory elements, including potential transcription factor binding sites, contribute to the gene's inducible expression, though specific motifs remain under active characterization. Known genetic variants in TBK1 include common polymorphisms such as rs4075094, which influences ALS susceptibility through rare and common allele effects.^[9] Loss-of-function mutations, often frameshift, nonsense, or splice-site alterations, are implicated in amyotrophic lateral sclerosis and frontotemporal dementia, reducing gene dosage and disrupting kinase function.^[10] Splicing variants, such as those affecting exon inclusion, can impair transcript stability and lead to haploinsufficiency.^[10] TBK1 exhibits high evolutionary conservation, with the protein sequence showing 94% identity between human and mouse orthologs, underscoring its essential role in innate immunity across mammals.^[2] The mouse Tbk1 ortholog resides on chromosome 10 (coordinates 121,382,360–121,422,692 in GRCm39), facilitating robust model organism studies.^[11] In non-mammalian species, such as fish and birds, orthologs display sequence divergences, particularly in regulatory domains, reflecting specialized adaptations in antiviral responses. Alternative splicing of TBK1 yields multiple isoforms, though primarily at the gene level without altering core exon architecture.

Tissue and Cellular Expression

TBK1 exhibits low basal expression across most human tissues, consistent with its role as a serine/threonine kinase involved in innate immune signaling. Data from the GTEx consortium reveal that median transcripts per million (TPM) values are generally modest, but elevated in immune-relevant sites such as the spleen, lung, and whole blood, where expression reaches higher levels indicative of readiness for pathogen sensing. Single-cell RNA sequencing analyses further demonstrate enriched expression in specific immune cell types, including macrophages (mean normalized counts per million, nCPM: 90.5), conventional dendritic cells (nCPM: 59.8), and B cells (nCPM: 54.0), underscoring its prominence in myeloid and lymphoid lineages.^[12] TBK1 gene expression is dynamically upregulated in response to immune stimuli, reflecting a feedback mechanism that amplifies antiviral and inflammatory pathways. Viral infections, such as duck enteritis virus, induce significant increases in TBK1 mRNA alongside IFN-β, as observed in both in vivo and in vitro models, suggesting a role in sustaining type I interferon responses. Lipopolysaccharide (LPS), a bacterial endotoxin, activates TBK1 in macrophages via phosphorylation, promoting downstream interferon production and linking it to Toll-like receptor-mediated immunity.^[13] RNA-seq datasets from GTEx corroborate these patterns, showing peak expression in the spleen and lung—tissues frequently exposed to microbial threats.^[14] During immune activation, TBK1 expression intensifies in lymphoid tissues, supporting adaptive responses such as T-cell homeostasis and cytokine production in dendritic cells. In disease contexts, particularly cancers, TBK1 shows altered patterns; for instance, it is overexpressed in glioblastoma samples compared to normal brain tissue, correlating with poorer patient prognoses and potentially contributing to tumor immune evasion. These expression dynamics highlight TBK1's integration into broader innate immune functions without delving into post-translational modifications.^[15]

Protein Structure and Regulation

Domain Architecture

TANK-binding kinase 1 (TBK1) is a serine/threonine kinase composed of 729 amino acids, with a molecular mass of approximately 84 kDa, and it predominantly exists as a monomer under basal conditions.^[16] The protein's modular architecture is critical for its biochemical properties, featuring an N-terminal kinase domain (KD) spanning residues 1–307, which harbors the catalytic core including the conserved ATP-binding G-loop motif (GxGxxG, residues 14–19) essential for nucleotide binding and phosphate transfer.^[17]^[7] Adjacent to the KD is the ubiquitin-like domain (ULD, residues 308–384), which serves as a ubiquitin-binding domain (UBD) to facilitate cargo recognition and interdomain regulation within the protein.^[18] The C-terminal region contains two coiled-coil domains—CCD1 (residues 407–657, also known as the scaffold/dimerization domain or SDD) and CCD2 (residues 658–713)—that promote oligomerization through helical interactions.^[18] Crystal structures, such as that of the dimeric form (PDB: 4IWO), illustrate how the SDD interfaces with the KD and ULD to stabilize the overall fold and enable trans-autophosphorylation.^[17] TBK1 undergoes key post-translational modifications that influence its structural dynamics. Phosphorylation at Ser172 within the KD activation loop induces conformational changes necessary for catalytic competence, as observed in structural models.^[16] SUMOylation at Lys694 in the C-terminal coiled-coil region modulates adaptor interactions and enhances structural integrity without disrupting the core domains.^[19] The canonical isoform 1 (729 amino acids) represents the full-length protein, while shorter variants, such as isoform 2 (575 amino acids), lack portions of the C-terminal SDD due to alternative splicing, leading to reduced stability and altered regulatory capacity.^[20] These isoforms differ in their ability to form stable oligomers, with the truncated forms exhibiting diminished scaffold-mediated interactions.^[21]

Activation and Regulatory Mechanisms

TBK1 activation primarily occurs through autophosphorylation at serine 172 (Ser172) within its kinase domain activation loop, a process that requires dimerization mediated by the scaffold/dimerization domain (SDD).^[22] This trans-autophosphorylation event induces conformational changes that enable substrate binding and catalytic activity, with biophysical studies indicating that dimer formation is essential for efficient phosphorylation, as mutants disrupting the SDD interface exhibit reduced autophosphorylation and kinase function.^[23] Kinetic analyses of TBK1's kinase domain reveal an ATP Km of approximately 10 μM under physiological conditions, underscoring its efficiency in nucleotide utilization during activation.^[24] Upstream signals further promote TBK1 activation through transphosphorylation at Ser172 by related kinases such as IKKε and TAK1, particularly in response to Toll-like receptor or cytokine stimuli.^[24] Additionally, K63-linked ubiquitination of TBK1 at lysines 30 and 401, facilitated by the E3 ligase activity involving TRAF3, enhances TBK1 recruitment to signaling complexes and stabilizes its dimeric form for subsequent autophosphorylation.^[22] These modifications collectively amplify TBK1's responsiveness to innate immune triggers without altering its core catalytic mechanism. Negative regulation of TBK1 ensures controlled signaling duration, with protein phosphatase 2A (PP2A) directly dephosphorylating Ser172 to deactivate the kinase and attenuate downstream interferon responses. Optineurin-mediated selective autophagy further limits TBK1 activity by promoting its ubiquitination and lysosomal degradation, particularly during prolonged stimulation, thereby preventing excessive inflammation.^[25] A key feedback loop involves IRF3 activation leading to type I interferon production, which in turn induces expression of suppressors like SIKE1 that bind and inhibit TBK1, closing the signaling circuit.^[26] Allosteric regulation fine-tunes TBK1 through scaffold proteins such as TANK, which binds the kinase to stabilize its active dimeric conformation and facilitate substrate access without directly modifying catalytic residues.^[27] Biophysical studies, including size-exclusion chromatography and multi-angle light scattering, demonstrate that dimer stability is sensitive to pH and ionic conditions, with higher salt concentrations or neutral pH promoting the oligomeric state essential for activation.^[23]

Biological Functions

Innate Immune Responses

TANK-binding kinase 1 (TBK1) serves as a central mediator in innate immune responses by integrating signals from pattern recognition receptors to orchestrate antiviral and antibacterial defenses. Upon detection of viral or bacterial pathogens, TBK1 is activated downstream of cytosolic sensors such as retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), which recognize double-stranded RNA from RNA viruses, as well as endosomal Toll-like receptors TLR3 and TLR4, which detect viral dsRNA and bacterial lipopolysaccharide (LPS), respectively.^[28]^[29] This activation culminates in the phosphorylation and nuclear translocation of interferon regulatory factor 3 (IRF3), driving robust production of type I interferons (IFNs), including IFN-α and IFN-β, which establish an antiviral state in neighboring cells and amplify immune activation.^[30] In addition to antiviral immunity, TBK1 regulates the production of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in macrophages, contributing to the inflammatory cascade that recruits and activates immune cells at infection sites. Through non-canonical signaling, TBK1 promotes these cytokines independently of canonical NF-κB pathways in some contexts, enhancing pathogen clearance while preventing excessive tissue damage.^[18]^[31] Studies in TBK1-deficient macrophages demonstrate reduced IL-6 and TNF-α secretion upon LPS stimulation, underscoring its essential role in mounting effective inflammatory responses.^[32] At the cellular level, TBK1-driven type I IFN signaling promotes apoptosis in virus-infected cells, limiting viral replication and spread by inducing programmed cell death pathways. This process is particularly evident in infected epithelial and immune cells, where IFN-mediated upregulation of pro-apoptotic factors restricts pathogen propagation.^[33] Furthermore, TBK1 facilitates dendritic cell (DC) maturation, enabling these antigen-presenting cells to upregulate costimulatory molecules and migrate to lymph nodes, thereby bridging innate and adaptive immunity. In TBK1-deficient DCs, maturation is impaired, leading to diminished T cell priming and weaker overall immune responses.^[34]^[35] Genetic studies in Tbk1-/- mice reveal profound impairments in innate immunity, with knockout animals exhibiting severely reduced type I IFN production and heightened susceptibility to RNA viruses like Sendai virus, resulting in uncontrolled viral replication and increased mortality.^[29] Similarly, in bacterial infection models such as Streptococcus pneumoniae pneumonia, myeloid-specific TBK1 deficiency leads to decreased survival rates compared to wild-type mice, highlighting its role in host defense beyond antiviral responses.^[36] TBK1's function is evolutionarily conserved across vertebrates, with high sequence homology enabling similar innate immune activation in diverse species, including bats and fish, where it supports pathogen resistance and survival during infections.^[37]^[38]

Autophagy and Cellular Homeostasis

TBK1 plays a pivotal role in selective autophagy by phosphorylating key autophagy receptors, thereby facilitating the targeting and degradation of ubiquitinated cargo. Specifically, TBK1 phosphorylates optineurin (OPTN) at serine 177 within its LC3-interacting region (LIR), which enhances OPTN's affinity for both ubiquitin chains and LC3/GABARAP proteins on the autophagosomal membrane. This phosphorylation creates a positive feedback loop, recruiting additional TBK1 to ubiquitinated targets and amplifying the autophagic response. In the context of xenophagy, this mechanism promotes the clearance of intracellular pathogens such as Salmonella enterica, where ubiquitinated bacteria are selectively engulfed and degraded, restricting bacterial proliferation. Similarly, TBK1 phosphorylates SQSTM1/p62 at serine 403 in its LIR domain, boosting p62's ubiquitin-binding capacity and its interaction with LC3, which supports the selective autophagic engulfment of ubiquitinated substrates.^[39] In mitophagy, TBK1 coordinates the removal of damaged mitochondria through collaboration with the E3 ubiquitin ligase Parkin. Upon mitochondrial depolarization, Parkin ubiquitinates outer mitochondrial membrane proteins, creating docking sites for autophagy receptors like OPTN and NDP52, which in turn recruit TBK1 to the damaged organelle. Activated TBK1 then phosphorylates these receptors—OPTN at S177 and NDP52 at multiple sites in its LIR—to strengthen their ubiquitin and LC3 binding, thereby driving autophagosome formation around the ubiquitinated mitochondria.^[25] This process ensures the efficient clearance of dysfunctional mitochondria, preventing the accumulation of reactive oxygen species (ROS) that could otherwise trigger oxidative stress and cellular damage.^[40] Disruption of TBK1 activity impairs this ubiquitination-dependent mitophagy pathway, leading to mitochondrial accumulation and heightened ROS levels. Beyond autophagy, TBK1 contributes to cellular homeostasis by regulating proliferation, polarity, and survival signaling. In non-stressed conditions, TBK1 directly phosphorylates AKT at threonine 308 and serine 473, activating it independently of upstream kinases like PDK1 and mTORC2, which promotes cell survival and inhibits apoptosis through downstream targets such as FOXO transcription factors. This anti-apoptotic function supports basal cellular maintenance and proliferation, particularly in epithelial cells where TBK1-AKT crosstalk influences polarity. For instance, TBK1 activation of AKT drives epithelial-mesenchymal transition (EMT) by phosphorylating GSK-3β and upregulating ZEB1, processes that modulate cell polarity and migration while maintaining tissue integrity under homeostatic cues.^[41] Dysregulation of TBK1 disrupts these homeostatic balances, with implications for neurodegeneration. Loss-of-function mutations in TBK1, common in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), impair phosphorylation of autophagy receptors like OPTN and p62, leading to defective selective autophagy and accumulation of protein aggregates such as TDP-43.^[42] In mouse models of ALS/FTD, Tbk1 deletion reproduces locomotor deficits and behavioral symptoms through autophagy disruption, highlighting TBK1's essential role in neuronal homeostasis. While hyperactivation scenarios are less documented, altered TBK1 signaling can exacerbate autophagic flux imbalances, contributing to neuronal loss in tauopathy models where TBK1-tau interactions promote hyperphosphorylation and excessive cargo overload.

Signaling Pathways

NF-κB and Inflammatory Signaling

TANK-binding kinase 1 (TBK1) plays a significant role in the canonical NF-κB pathway, particularly in response to Toll-like receptor (TLR) signaling. Upon stimulation of TLR3 or TLR4, TBK1 is recruited via the adaptor protein TRIF and TRAF3, contributing to the activation of NF-κB by phosphorylating IκBα at serine 32, which promotes its ubiquitination and proteasomal degradation, thereby facilitating the nuclear translocation of NF-κB dimers such as p50/RelA.^[43] Additionally, TBK1 phosphorylates the RelA subunit (p65) at serine 536, enhancing its transcriptional activity and amplifying the expression of pro-inflammatory genes in macrophages and other innate immune cells.^[43]^[5] In the non-canonical NF-κB pathway, TBK1 interacts with NF-κB-inducing kinase (NIK) and IKKα to exert regulatory control, primarily through negative feedback mechanisms essential for B-cell homeostasis. TBK1 phosphorylates NIK, leading to its ubiquitination and proteasomal degradation, which attenuates the processing of p100 to p52 and subsequent RelB/p52 dimer formation.^[44] This regulation is critical for B-cell survival in response to signals from BAFFR and CD40, preventing excessive non-canonical NF-κB activation that could disrupt lymphoid organogenesis and contribute to autoimmune conditions.^[44] TBK1's involvement in NF-κB signaling drives inflammatory outputs, particularly the regulation of pro-inflammatory genes such as COX-2 in chronic inflammatory settings. In vitro studies using LPS-stimulated macrophages demonstrate that TBK1 knockdown reduces NF-κB-dependent COX-2 induction by approximately 50%, highlighting a dose-dependent role in amplifying inflammatory mediator production.^[45] In models of arthritis, such as osteoarthritis, pharmacological inhibition of TBK1 suppresses NF-κB activation, reducing joint inflammation and cartilage degradation, underscoring its contribution to chronic disease progression.^[46] TBK1 integrates NF-κB signaling with the mitogen-activated protein kinase (MAPK) pathway, facilitating crosstalk that can amplify inflammatory responses like cytokine storms. By negatively regulating both pathways in myeloid cells, TBK1 limits excessive activation of JNK and p38 MAPK alongside NF-κB, thereby controlling the production of cytokines such as TNF-α and IL-6; its deficiency enhances this integration, leading to heightened inflammation in conditions like colitis.^[47]

IRF3 and Antiviral Pathways

TANK-binding kinase 1 (TBK1) plays a central role in the antiviral response by phosphorylating interferon regulatory factor 3 (IRF3) at specific serine residues, primarily Ser396 and Ser398, within its C-terminal domain.^[48] This phosphorylation disrupts IRF3's autoinhibitory conformation, promoting its dimerization and subsequent binding to interferon-stimulated response elements (ISREs) in the promoters of type I interferon genes. The process is essential for transactivating antiviral genes, distinguishing it from other signaling outputs by its specificity for interferon production over broader inflammatory responses. Upon activation of retinoic acid-inducible gene I (RIG-I) by viral RNA, TBK1 and IKKε are recruited to the MAVS adaptor complex to phosphorylate IRF3. This assembly occurs rapidly post-stimulation, with TBK1 autophosphorylation at Ser172 and IRF3 modification detectable within 15 minutes in response to viral ligands like poly(I:C).^[49] The complex's formation ensures coordinated signaling from upstream adaptors such as MAVS, amplifying the antiviral transcriptional program while maintaining spatial organization at mitochondrial or peroxisomal membranes. The TBK1-IRF3 axis drives the induction of type I interferons (IFN-α and IFN-β), which in turn upregulate interferon-stimulated genes (ISGs) such as Mx1, a dynamin-like GTPase that inhibits viral replication. In vesicular stomatitis virus (VSV) infection models, TBK1 deficiency impairs IFN-β production and ISG expression, resulting in enhanced viral replication and reduced host survival, underscoring the pathway's efficacy against RNA viruses.^[50] Representative studies demonstrate that Mx1-mediated inhibition of VSV nucleocapsid assembly directly correlates with TBK1-dependent IFN signaling strength.^[51] TBK1 also mediates IRF3 phosphorylation in the cGAS-STING pathway, where cytosolic DNA activates STING to recruit TBK1, leading to IRF3 activation and type I IFN production in response to DNA viruses and other threats.^[52] Autophagy provides negative feedback to limit TBK1 activity and prevent excessive interferon production. This involves selective autophagy receptors like NDP52 recognizing ubiquitinated TBK1, promoting its lysosomal turnover.^[53] Such regulation ensures resolution of the antiviral response, avoiding immunopathology from prolonged signaling.

Protein Interactions

Direct Binding Partners

TANK (TRAF-family member associated NF-κB activator) is a core direct binding partner of TBK1, interacting through the coiled-coil 2 (CC2) domain in the C-terminal region of TBK1. This interaction was identified via yeast two-hybrid screening and confirmed by co-immunoprecipitation assays, where TANK, along with related adaptors Sintbad and NAP1, competitively binds the CC2 domain to facilitate TBK1 recruitment in signaling complexes.^[54] In the context of RIG-I-like receptor signaling, mitochondrial antiviral-signaling protein (MAVS) serves as a key scaffold that indirectly engages TBK1 through adaptor proteins.^[55] Adapter proteins such as TRAF2 and TRAF3 directly interact with TBK1, promoting its ubiquitination and activation; these bindings were detected through affinity purification followed by mass spectrometry and co-immunoprecipitation, with TRAF3 particularly essential for linking upstream sensors to TBK1 in innate immune pathways.^[54] Optineurin binds TBK1 via its N-terminal coiled-coil domain, independent of its ubiquitin-binding domain (UBD), and TBK1-mediated phosphorylation of optineurin enhances its binding to ubiquitin chains and recruitment to autophagic structures, as shown in co-immunoprecipitation and in vitro binding assays.^[56]^[57] TBK1 forms heterodimers with the related kinase IKKε, sharing structural similarities in their kinase domains and scaffold/dimerization regions; this association, sub-stoichiometric in nature, was evidenced by co-immunoprecipitation and gel filtration analyses, contrasting with TBK1 homodimerization, and supports redundant roles in interferon induction.^[54] The molecular chaperone Hsp90 directly associates with TBK1 to assist in its folding, stability, and maturation, as demonstrated by co-immunoprecipitation and cycloheximide chase assays showing that Hsp90 inhibition leads to rapid TBK1 degradation via the proteasome.^[58] These chaperone interactions maintain TBK1 levels under basal conditions, briefly supporting its availability for pathway activation upon stimulation.

Functional Interaction Networks

TBK1 functions within intricate protein interaction networks that orchestrate innate immune signaling, autophagy, and metabolic regulation, often emerging from dynamic multi-protein complexes rather than isolated interactions. These networks integrate TBK1's kinase activity with upstream sensors and downstream effectors, enabling context-specific responses to cellular stress, infection, and homeostasis. Proteomic mapping, including high-confidence interaction datasets, underscores TBK1's centrality in motifs involving ubiquitination and phosphorylation hubs that amplify signaling efficiency.^[59] In signalosomes, TBK1 assembles dynamically within the IPS-1/MAVS complex to propagate antiviral innate immune responses. Upon viral detection by RIG-I-like receptors, MAVS forms prion-like aggregates on mitochondria, recruiting TBK1 through K27-linked ubiquitination at MAVS K325 mediated by TRIM21, which facilitates TBK1 phosphorylation of MAVS at S442 and subsequent IRF3 activation. This ubiquitination-dependent hub ensures transient signalosome formation, balancing potent antiviral interferon production with prevention of excessive inflammation via regulatory dephosphorylation by PPM1A.^[60]^[61]^[62] Autophagy networks position TBK1 as a key integrator with ULK1 and AMPK for mitophagy initiation, particularly under energetic stress. AMPK activation promotes phosphorylation of TBK1 at Ser172, enhancing its role in autophagosome engulfment of damaged mitochondria independently of the PINK1-Parkin pathway, while ULK1 phosphorylation at Ser555 by AMPK further coordinates this process. In selective autophagy, TBK1 collaborates with NDP52 to spatiotemporally control ULK1 recruitment to ubiquitinated cargoes, forming network motifs that couple mitochondrial fission—via MFF phosphorylation—with autophagic clearance.^[63]^[64] Crosstalk hubs reveal TBK1's overlap with the PI3K/AKT/mTOR pathway, linking immune signaling to proliferative responses in cancer. TBK1 directly phosphorylates mTOR at S2159 in response to growth factors like EGF or innate agonists via TLR3/4, activating mTORC1 to drive cell growth and survival without relying on canonical PI3K/AKT inputs in certain contexts. This temporal integration, evident in infection models where TBK1 sustains mTORC1 during early immune activation, promotes oncogenic proliferation in KRAS-mutant tumors by bridging inflammation and metabolism.^[65] Pathological networks highlight altered TBK1 connectivity, such as in ALS where mutations disrupt the TBK1-OPTN axis critical for autophagy. Missense variants like E696K impair TBK1-OPTN binding and OPTN phosphorylation at S177, reducing LC3 recruitment and autophagosome formation, which destabilizes broader network stability through defective dimerization and substrate specificity. These changes manifest as haploinsufficient connectivity losses in ubiquitin-mediated clearance pathways, exacerbating protein aggregation without fully abolishing kinase activity.^[66]^[67]

Clinical Significance

Associations with Diseases

TANK-binding kinase 1 (TBK1) loss-of-function mutations, including nonsense and frameshift variants that lead to haploinsufficiency, have been identified as a cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), often presenting as an ALS/FTD spectrum disorder.^[10] These mutations impair TBK1's role in autophagy by disrupting phosphorylation of autophagy receptors such as optineurin (OPTN), contributing to protein aggregate accumulation in neurons.^[68] For example, the missense mutation p.Arg573Gly reduces TBK1 kinase activity and autophagic flux in patient-derived cells.^[69] The prevalence of such mutations is approximately 1% in sporadic ALS cases and up to 4% in familial ALS/FTD cohorts.^[70] In cancer, TBK1 overexpression is observed in breast and lung tumors, where it supports tumor progression and metastasis. In breast cancer, elevated TBK1 levels correlate with estrogen receptor-positive subtypes and are linked to tamoxifen resistance and increased metastatic potential through enhanced AKT signaling.^[71]^[18] Similarly, in non-small cell lung cancer, co-expression of TBK1 with IKKε is associated with distant metastasis in stage I patients.^[72] TBK1 sustains KRAS-mutant lung tumor growth by phosphorylating and stabilizing AKT, promoting cell survival and invasion.^[73] Somatic alterations in TBK1, including amplifications, occur in gliomas, though at lower frequencies, contributing to oncogenic signaling.^[74] TBK1 dysregulation contributes to autoimmune diseases through altered inflammatory signaling. In rheumatoid arthritis (RA), increased TBK1 activity in fibroblast-like synoviocytes drives production of proinflammatory chemokines like IP-10, exacerbating synovial inflammation; gain-of-function-like hyperactivation of TBK1-STING signaling has been implicated in autoinflammatory arthritis models.^[75]^[76] Homozygous loss-of-function TBK1 mutations, such as p.W619* and p.R440*, cause early-onset autoinflammatory syndromes resembling RA with polyarthritis, vasculitis, and recurrent fever, driven by TNF-mediated cell death.^[77] For inflammatory bowel diseases like Crohn's disease, TBK1 variants indirectly associate via impaired autophagy pathways, with interacting proteins like NDP52 showing genetic links to disease susceptibility.^[78] TBK1 deficiency heightens susceptibility to viral infections, particularly herpes simplex virus (HSV). Heterozygous TBK1 mutations impair TLR3-dependent type I interferon production, leading to herpes simplex encephalitis (HSE) in affected individuals; patient fibroblasts exhibit increased HSV-1 replication.^[79] Cohort studies of HSE patients reveal TBK1 variants in approximately 3-5% of cases, underscoring its role in central nervous system antiviral defense. Complete TBK1 inactivation further exacerbates vulnerability to HSV and other viruses like vesicular stomatitis virus, as observed in genetic deficiency models.^[80]

Therapeutic Implications and Inhibitors

TBK1 has emerged as a promising therapeutic target in diseases involving dysregulated innate immune signaling, such as amyotrophic lateral sclerosis (ALS), various cancers, and autoimmune disorders, where its inhibition can mitigate excessive type I interferon production and inflammation.^[81] In ALS, for instance, TBK1 mutations contribute to pathogenesis, and pharmacological inhibition has shown potential to alleviate symptoms in preclinical models.^[82] Small-molecule inhibitors of TBK1 primarily fall into ATP-competitive and allosteric classes. ATP-competitive inhibitors, such as BX795, bind the kinase's active site and potently suppress TBK1 activity with an IC₅₀ of approximately 15 nM, though they often exhibit off-target effects on related kinases like IKKε.^[83] Allosteric inhibitors, exemplified by Compound II (a 6-aminopyrazolopyrimidine derivative), target the scaffold/dimerization domain (SDD) to disrupt TBK1 dimerization and autophosphorylation, achieving an IC₅₀ of 20 nM in cellular assays and demonstrating efficacy in reducing interferon responses without directly competing for ATP binding.^[84] These inhibitors have been evaluated in therapeutic contexts, including repurposed amlexanox—a selective TBK1/IKKε blocker—that attenuates the TBK1-IRF3 axis in cancer models, leading to reduced tumor growth in lung, breast, and endometrial xenografts.^[85] In autoimmune settings, Compound II ameliorates disease phenotypes in mouse models of systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS) by suppressing TBK1-driven IFN signatures.^[84] Despite these advances, challenges in TBK1 inhibition include achieving selectivity over the canonical IKKβ kinase, as many compounds like BX795 cross-react, potentially disrupting NF-κB signaling and causing unintended inflammatory modulation.^[86] Toxicity concerns arise from broad immune suppression, increasing susceptibility to viral infections, while preclinical pharmacodynamic studies indicate that at least 70-80% TBK1 inhibition is required for robust efficacy in inflammatory models.^[81] No TBK1-specific inhibitors have advanced to phase III clinical trials as of 2025, though amlexanox has undergone phase II testing for metabolic disorders with evidence of TBK1 modulation, supporting its repurposing for ALS and oncology.^[82] Emerging strategies address these limitations through protein degradation and nucleic acid-based approaches. PROTACs, such as VHL-recruiting chimeras (e.g., compound 3i with a DC₅₀ of 12 nM and >95% degradation efficiency), selectively induce TBK1 ubiquitination and proteasomal degradation, offering superior durability over reversible inhibition and potential utility in autoimmune diseases by avoiding kinase rebound.^[87] Preclinical siRNA delivery systems, including nanoparticle-conjugated anti-TBK1 siRNAs, have demonstrated autophagy induction and immune pathway modulation in glioblastoma models, with ongoing exploration for broader neurodegenerative and oncologic applications.^[88]

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[20]
An updated evolutionary and structural study of TBK1 reveals highly ...
Sep 17, 2022 · The present study sought to elucidate the role of the TBK1 protein in Amyotrophic Lateral Sclerosis (ALS), a human neurodegenerative disorder.Missing: common | Show results with:common
[21]
SUMO modification of TBK1 at the adaptor-binding C-terminal coiled ...
SUMO modification at K694 contributes to the antiviral function of TBK1 and accordingly the viral protein Gam1 antagonizes this posttranslational modification.
[22]
Serine/threonine-protein kinase TBK1 - UniProtKB
Protein Serine/threonine-protein kinase TBK1. Gene TBK1. Status UniProtKB unreviewed (TrEMBL). Organism Homo sapiens (Human). Amino acids 575 (go to sequence).
[23]
A Novel Transcript Isoform of TBK1 Negatively Regulates Type I IFN ...
Sep 30, 2020 · In mammals, multiple mechanisms including posttranslational modification of TBK1, kinase activity modulation, and prevention of functional TBK1 ...
[24]
Phosphorylation of OPTN by TBK1 enhances its binding to Ub ...
Mar 30, 2016 · Here, we provide evidence that TBK1 integrates upstream Ub-dependent signaling events by phosphorylating the autophagy receptor OPTN in the Ub- ...
[25]
Mechanism of Endogenous Regulation of the Type I Interferon ...
Our studies demonstrate for the first time that SIKE functions as a TBK1 substrate and inhibits TBK1-mediated IRF3 phosphorylation by forming a high affinity ...
[26]
IKKε and TBK1 are essential components of the IRF3 signaling ...
Apr 14, 2003 · IKKε and TBK1 have a pivotal role in coordinating the activation of IRF3 and NF-κB in the innate immune response.
[27]
IFN-IRF3 Gene Expression Defective in Tbk1-Deficient MEFs
We show that TBK1 is required for the activation and nuclear translocation of IRF3 in these cells. Moreover, Tbk1 -/- MEFs show marked defects in IFN-α and -β, ...
[28]
IKKepsilon and TBK1 are essential components of the IRF3 ...
IKKepsilon and TBK1 have a pivotal role in coordinating the activation of IRF3 and NF-kappaB in the innate immune response.
[29]
Desuccinylation of TBK1 by SIRT5 regulates inflammatory response ...
Dec 24, 2024 · Consequently, macrophages deficient in SIRT5 exhibit impaired LPS-induced TBK1 activation and reduced production of IFNβ, IL-6, and TNF-α.
[30]
Desuccinylation of TBK1 by SIRT5 regulates inflammatory response ...
Dec 13, 2024 · These findings reveal a novel mecha- nism by which SIRT5 modulates TBK1 activity and macrophage-mediated inflammation during sepsis.<|control11|><|separator|>
[31]
TBK1 is paradoxical in tumor development: a focus on the pathway ...
TBK1 acts as a pivotal node within the innate immune pathway, mediating anti-tumor immunity through the activation of innate immune responses.
[32]
TANK-Binding Kinase 1 in the Pathogenesis and Treatment ... - MDPI
TBK1 drives immune cells to participate in the inflammatory response by activating the NF-κB and interferon regulatory factor signaling pathways in immune cells ...Tank-Binding Kinase 1 In The... · 2. Role Of Tbk1 In Immune... · 3. Role Of Tbk1 In...
[33]
The kinase TBK1 functions in dendritic cells to regulate T cell ...
Xiao et al. demonstrate that a protein kinase, TBK1, regulates the function of dendritic cells in mediating immune responses.
[34]
TBK1's Role in Bacterial Pneumonia - ATS Journals
Apr 1, 2022 · In this new publication, the authors demonstrate reduced survival of TBK1-deficient mice upon S. pneumoniae infection compared with control animals.
[35]
Conserved function of bat TBK1 in activating innate immunity ...
Jul 28, 2025 · In mammals, TANK binding kinase 1(TBK1) is a crucial central node protein in the innate immune system. TBK1 can receive activation signals ...
[36]
A novel TBK1/IKKϵ is involved in immune response and interacts ...
Inhibitor of κB kinase (IKK) family proteins are key signaling molecules in the animal innate immune system and are considered master regulators of inflammation ...
[37]
TBK1 controls autophagosomal engulfment of polyubiquitinated ...
Our results suggest that TBK1-mediated p62 phosphorylation regulates the efficient autophagosomal engulfment of mitochondria as an acute response and that OPTN– ...Tbk1 Controls Autophagosomal... · Tbk1 Phosphorylates P62... · Optineurin Recruits Tbk1 To...<|control11|><|separator|>
[38]
RAB7A phosphorylation by TBK1 promotes mitophagy via the PINK ...
Nov 21, 2018 · Removal of damaged mitochondria is orchestrated by a pathway involving the PINK1 kinase and the PARKIN ubiquitin ligase.Tbk1 Directly And... · Defective Mitophagy In Cells... · Tbk1 Phosphoproteomics
[39]
Inhibition of TBK1 attenuates radiation-induced epithelial ... - Nature
Jan 27, 2014 · Our findings reveal that TBK1 signaling regulates radiation-induced EMT by controlling GSK-3β phosphorylation and ZEB1 expression.
[40]
TBK1: a new player in ALS linking autophagy and neuroinflammation
Feb 2, 2017 · TBK1 is required for efficient cargo recruitment in autophagy; mutations in TBK1 may result in impaired autophagy and contribute to the accumulation of protein ...
[41]
The Pivotal Role of TBK1 in Inflammatory Responses Mediated by ...
TBK1 is a serine/threonine-protein kinase which regulates antiviral defense, host-virus interaction, and immunity. It is ubiquitously expressed in mouse stomach ...2.1. Tbk1 · 2.4. Tbk1-Activated... · 4.2. Tbk1 Inhibitor As A...
[42]
NF-κB signaling in inflammation - Nature
Jul 14, 2017 · The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses.
[43]
The non-canonical NF-κB pathway in immunity and inflammation
Similar to IKKα, the IKK-related kinase TANK-binding kinase 1 (TBK1) phosphorylates NIK to promote NIK degradation, which occurs in B cells in response to BAFFR ...
[44]
TANK-binding kinase 1 (TBK1) modulates inflammatory ...
May 23, 2015 · It is activated by viral infections and inflammatory mediators and has therefore been associated with viral diseases, obesity, and rheumatoid ...
[45]
TBK1 pharmacological inhibition mitigates osteoarthritis through ...
Jun 28, 2024 · Pharmacological inhibition of TBK1 with BX795 protects articular cartilage by inhibiting the activation of the cGAS–STING and TLR3–TRIF signaling pathways.Missing: rs2235650 | Show results with:rs2235650
[46]
NF-κB in biology and targeted therapy: new insights and ... - Nature
Mar 4, 2024 · Evidence of NF-κB signaling's interaction with MAPK signaling has primarily centered on JNK signaling. TAK1 serves as an upstream kinase for ...
[47]
Contribution of Ser386 and Ser396 to activation of interferon ...
... TBK1 can directly phosphorylate full-length IRF-3. Phosphorylation at residues in site 2 (Ser396 to Ser405) alleviated autoinhibition to allow interaction ...
[48]
Interferon Regulatory Factor 3 Is Regulated by a Dual ...
Using purified proteins we show that TBK1 can directly phosphorylate full-length IRF-3 in vitro. Phosphorylation at residues in site 2 (Ser396—Ser405) ...
[49]
Identification of TBK1 complexes required for the phosphorylation of ...
Although it is well established that the activation of TBK1 and the phosphorylation of IRF3 are key events in the TLR3/4 signalling pathway leading to IFNβ gene ...
[50]
The STING/TBK1/IRF3/IFN type I pathway is defective in cystic fibrosis
Feb 26, 2023 · Moreover, Figure 1A shows that 4 hours of infection is the optimal time to induce massive IRF3 phosphorylation at Serine 396, which is used as a ...Missing: course | Show results with:course
[51]
Autophagy Inhibition Dysregulates TBK1 Signaling and Promotes ...
Autophagy inhibition has been proposed for treatment of KRAS-driven cancer, but this strategy resulted in a protumorigenic feedback loop that activated.
[52]
Selective autophagy controls the stability of TBK1 via NEDD4 ... - NIH
Jul 13, 2021 · NEDD4 targets TBK1 for degradation via ubiquitination, which is then recognized by NDP52 for selective autophagic degradation.
[53]
Functional Dissection of the TBK1 Molecular Network - PMC
TANK, Sintbad and NAP1 all bind to the coiled-coil 2 in TBK1 and compete for TBK1 binding, suggesting that they may act as recruiting adaptors. Deletion or ...
[54]
MAVS activates TBK1 and IKKε through TRAFs in NEMO ... - NIH
Nov 10, 2017 · Fully activated TBK1/IKKε and IKKa/β phosphorylate and activate transcriptional factors IRF3/7 and NF-κB respectively, which translocate into the nucleus.
[55]
Phosphorylation of OPTN by TBK1 enhances its binding to Ub ... - NIH
Mar 30, 2016 · Here, we provide evidence that TBK1 integrates upstream Ub-dependent signaling events by phosphorylating the autophagy receptor OPTN in the Ub- ...
[56]
Structural insights into the interaction and disease mechanism of ...
Sep 13, 2016 · Our study provides mechanistic insights into those currently known disease-causing optineurin and TBK1 mutations found in patients.Missing: deactivation | Show results with:deactivation
[57]
Hsp90 Regulates Activation of Interferon Regulatory Factor 3 and ...
Stability of TBK1 Was Dependent on Hsp90 Activity. Because TBK1 interacted with Hsp90, we wondered whether the chaperon activity of Hsp90 was essential for ...
[58]
None
Nothing is retrieved...<|control11|><|separator|>
[59]
https://string-db.org/network/9606.ENSP00000329967
[60]
https://doi.org/10.1038/s41467-018-05852-0
[61]
https://doi.org/10.1126/science.aaa2630
[62]
https://doi.org/10.1126/sciadv.1501889
[63]
https://doi.org/10.1096/fj.201903051R
[64]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212019/
[65]
https://doi.org/10.15252/embj.201696164
[66]
https://doi.org/10.1073/pnas.1915732116
[67]
ALS- and FTD-associated missense mutations in TBK1 ... - PubMed
Jun 15, 2021 · More than 90 distinct mutations in TBK1 are linked to amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia, including missense ...
[68]
Functional Characterization of a Familial ALS-Associated Missense ...
Feb 2, 2023 · The goal of this work was to elucidate the pathogenic mechanism of an ALS-associated missense mutation, p.Arg573Gly (R573G), in the TBK1 gene.
[69]
TBK1 is involved in programmed cell death and ALS ... - Nature
Mar 12, 2025 · Pathogenic mutations within the TBK1 gene leading to haploinsufficiency are causative of amyotrophic lateral sclerosis (ALS).
[70]
Elevated expression of TANK-binding kinase 1 enhances tamoxifen ...
Ectopic expression of TBK1 rendered breast cancer cells resistant to tamoxifen. TBK1 inhibition sensitized breast cancer cells to tamoxifen-induced cell death.
[71]
Expression and prognostic role of IKBKE and TBK1 in stage I ... - NIH
IKBKE+/TBK1+ co-expression was significantly obvious in patients with risk factors and with recurrence pattern of distant metastasis. Furthermore, IKBKE+/TBK1+ ...
[72]
TBK1 Provides Context-Selective Support of the Activated AKT ...
Emerging observations link dysregulation of TANK-binding kinase 1 (TBK1) to developmental disorders, inflammatory disease, and cancer.
[73]
TBK1 Inhibitor Exerts Antiproliferative Effect on Glioblastoma ... - PMC
Our results demonstrated that BX795 10 μM was able to reduce cell viability, showing antiproliferative effect in U87, U138, and primary GBM cells.
[74]
Synoviocyte innate immune responses: TANK-binding kinase-1 as a ...
May 25, 2011 · Based on the selective regulation of IP-10 in FLS, TBK1 appears to be the optimal IKK-related kinase to target in RA.
[75]
TBK1 recruitment to STING mediates autoinflammatory arthritis ...
These results demonstrate that TBK1 recruitment to STING mediates autoinflammatory arthritis independently of type I interferons.
[76]
Human TBK1 Deficiency Leads to Autoinflammation from TNF Death
Aug 19, 2021 · We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through ...
[77]
Association Between Variants of PRDM1 and NDP52 and Crohn's ...
The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat Immunol. 2009; 10:1215-1221. Crossref · Scopus (708).
[78]
Heterozygous TBK1 mutations impair TLR3 immunity and underlie ...
Neither of the two TBK1 variants was found in single nucleotide polymorphism (SNP) databases (NCBI dbSNP 135 and UCSC) or on sequencing of a panel of 1,050 ...
[79]
Hyper-Susceptibility to viral infections in patients with inactive TBK1
Mar 9, 2023 · Upon mutation-induced loss of TBK1 function, patients show an increased susceptibility to viral infections. Strikingly, if TBK1 is not expressed at all, this ...
[80]
Therapeutic potential of targeting TBK1 in autoimmune diseases ...
Jun 25, 2016 · This review summarizes recent advance on the pharmacological inhibition of TBK1 and its potential for treating autoimmune diseases and interferonopathies.Missing: implications | Show results with:implications
[81]
TBK1, a prioritized drug repurposing target for amyotrophic lateral ...
Mar 5, 2024 · After that, protein expression levels were evaluated employing Western blotting. However, the drug treatment method was slightly modified for ...
[82]
BX-795 inhibits HSV-1 and HSV-2 replication by blocking the JNK ...
Jan 23, 2017 · ... TBK1 is a negative regulator of HSV propagation. BX-795 inhibited IKKɛ and TBK1 with IC50 at 41 and 6 nmol/L in a cell-free system, respectively ...Missing: IC50 | Show results with:IC50
[83]
Inhibiting TBK1 by Compound II Ameliorates Autoimmune Disease ...
We found that Compound II is a potent and specific inhibitor of TBK1-mediated IFN response. Compound II inhibited polyinosinic-polycytidylic acid–induced immune ...Missing: allosteric SDD
[84]
TBK1 inhibitor amlexanox exerts anti-cancer effects against ... - NIH
This study highlights the potent anti-cancer effects of amlexanox against endometrial cancer by modulating AKT/NF-κB signaling.
[85]
Identification and Further Development of Potent TBK1 Inhibitors
Dec 26, 2014 · Here, the authors describe three potent PDK1 inhibitors, BX-795, BX-912, and BX-320 (IC50 = 11-30 nM) and their initial biol. characterization.<|separator|>
[86]
Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1
### Summary of PROTACs for TBK1 Degradation and Applications
[87]
A Nanoparticle-Conjugated Anti-TBK1 siRNA Induces Autophagy ...
Dec 11, 2021 · TBK1si/rGO-PEG exhibited anti-GBM activities by inhibiting TBK1 and autophagy, as well as activating apoptosis and cGAS-STING pathway.