TBK1

Official Full Name

TANK binding kinase 1

Organism

Homo sapiens

GeneID

29110

Background

The NF-kappa-B (NFKB) complex of proteins is inhibited by I-kappa-B (IKB) proteins, which inactivate NFKB by trapping it in the cytoplasm. Phosphorylation of serine residues on the IKB proteins by IKB kinases marks them for destruction via the ubiquitination pathway, thereby allowing activation and nuclear translocation of the NFKB complex. The protein encoded by this gene is similar to IKB kinases and can mediate NFKB activation in response to certain growth factors. The protein is also an important kinase for antiviral innate immunity response. [provided by RefSeq, Sep 2021]

Synonyms

NAK; T2K; AIARV; IIAE8; FTDALS4;

Bio Chemical Class

Kinase

Protein Sequence

MQSTSNHLWLLSDILGQGATANVFRGRHKKTGDLFAIKVFNNISFLRPVDVQMREFEVLKKLNHKNIVKLFAIEEETTTRHKVLIMEFCPCGSLYTVLEEPSNAYGLPESEFLIVLRDVVGGMNHLRENGIVHRDIKPGNIMRVIGEDGQSVYKLTDFGAARELEDDEQFVSLYGTEEYLHPDMYERAVLRKDHQKKYGATVDLWSIGVTFYHAATGSLPFRPFEGPRRNKEVMYKIITGKPSGAISGVQKAENGPIDWSGDMPVSCSLSRGLQVLLTPVLANILEADQEKCWGFDQFFAETSDILHRMVIHVFSLQQMTAHKIYIHSYNTATIFHELVYKQTKIISSNQELIYEGRRLVLEPGRLAQHFPKTTEENPIFVVSREPLNTIGLIYEKISLPKVHPRYDLDGDASMAKAITGVVCYACRIASTLLLYQELMRKGIRWLIELIKDDYNETVHKKTEVVITLDFCIRNIEKTVKVYEKLMKINLEAAELGEISDIHTKLLRLSSSQGTIETSLQDIDSRLSPGGSLADAWAHQEGTHPKDRNVEKLQVLLNCMTEIYYQFKKDKAERRLAYNEEQIHKFDKQKLYYHATKAMTHFTDECVKKYEAFLNKSEEWIRKMLHLRKQLLSLTNQCFDIEEEVSKYQEYTNELQETLPQKMFTASSGIKHTMTPIYPSSNTLVEMTLGMKKLKEEMEGVVKELAENNHILERFGSLTMDGGLRNVDCL

Open

Approved Drug

Clinical Trial Drug

Discontinued Drug

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Detailed Information

TBK1 (TANK-binding kinase 1) gene is located on human chromosome 12q14.2 and encodes a member of the IKK kinase family, specifically a serine/threonine kinase. The structure of the TBK1 protein includes an N-terminal kinase domain, a C-terminal dimerization domain, and a crucial Cys-89 residue, all of which are essential for its phosphorylation activity and interaction with other adaptor proteins. Unlike mammals, where the sequence is highly conserved, fish species like the black carp (Mylopharyngodon piceus) retain the antiviral function of TBK1 but have a significantly different regulatory mechanism—TRAF6, instead of TRAF3, is the major regulator of TBK1 in these species.

Biological Functions and Mechanisms

TBK1 plays a central role in the innate immune response. Upon detection of viral nucleic acids through pathways such as cGAS-STING or RIG-I-MAVS, TBK1 is recruited to the signaling complex and phosphorylates interferon regulatory factors IRF3 and IRF7, which are essential for the production of type I interferons (IFN-α/β). This forms a critical line of defense against viral infections. Interestingly, TBK1 activity is modulated by the cellular microenvironment: conditions like nutrient deprivation or high-density cell packing can enhance TBK1 sensitivity and boost antiviral defense capabilities. In addition to immune regulation, TBK1 promotes autophagosome maturation and pathogen clearance by phosphorylating autophagy receptors OPTN (Optineurin) and SMCR8. It also plays a dual role in regulating the mTORC1 complex—activating mTORC1 in response to growth factor signaling while inhibiting it through phosphorylation of RPTOR during stress conditions.

Pathophysiological Significance and Disease Associations

The dysfunction of TBK1 is associated with a wide range of diseases. In neurodegenerative diseases, the activity of TBK1 is significantly reduced in patients with amyotrophic lateral sclerosis (ALS) and in related mouse models. Research has shown that the integrity of the endoplasmic reticulum-mitochondria contact sites (MAM) is critical for maintaining TBK1 activity. Disruption of these sites impairs TBK1 activation, hindering stress granule formation and weakening the stress resistance of motor neurons, which ultimately leads to cell death. In cancer, TBK1 plays a role in promoting tumor growth in models of KRAS-mutant lung cancer through the TBK1-TBKBP1 signaling axis, activating mTORC1 via phosphorylation of PKCθ-Ser716, and inducing PD-L1 expression. This results in immune suppression and enhanced glycolysis, thereby inhibiting the function of CD4+/CD8+ T cells and contributing to the development of an immunosuppressive microenvironment. Furthermore, TBK1 gene loss-of-function mutations are strongly linked to frontotemporal dementia (FTD), with haploinsufficiency leading to uncontrolled neuroinflammation.

Figure 1. Activation of TBK1 by different upstream signaling. (Hu L, et al., 2024)

Clinical Applications and Translational Research

Therapeutic strategies targeting TBK1 have shown potential across various disease areas. In cancer immunotherapy, Amlexanox, an FDA-approved drug for oral ulcers, has been identified as a TBK1 inhibitor. In KRAS-mutant lung cancer mouse models, Amlexanox alone significantly reduced tumor burden and, when combined with anti-CTLA-4 antibodies, synergistically enhanced the proportion of IFN-γ+ effector T cells, reversing resistance to immune checkpoint inhibitors. In antiviral applications, TBK1 from black carp shows strong inhibition of Spring Viremia of Carp Virus (SVCV) and Grass Carp Reovirus (GCRV), suggesting its potential as a target for antiviral strategies in aquaculture. In neuroprotection, enhancing MAM-dependent activation of TBK1 may offer a novel intervention strategy for ALS.

Table 1. Regulatory Mechanisms and Targeting Strategies for TBK1 in Major Diseases

Disease Area	Key Regulatory Mechanism	Targeted Intervention Strategy	Preclinical Evidence
Cancer Immunotherapy	TBK1-TBKBP1 axis activating mTORC1, inducing PD-L1	Amlexanox monotherapy or in combination with anti-CTLA-4	Tumor burden reduced by 70% in KRAS lung cancer model
Antiviral Immunity	Phosphorylation of IRF3/7 to promote IFN production	Development of aquaculture vaccine adjuvants	Enhanced anti-GCRV ability in black carp model
Neurodegeneration	MAM disruption reduces TBK1 activity	MAM stabilizers or TBK1 activators	Improved motor function in ALS models

Challenges and Future Directions

One of the major challenges in TBK1-targeted therapy lies in its "double-edged sword" effect: excessive inhibition may weaken antiviral immunity, while selective activation could potentially increase cancer risks. Solutions include developing tissue-specific delivery systems or designing allosteric modulators. Additionally, exploring TBK1's immunomodulatory function in different cell types (such as regulatory T cells) and its involvement in metabolic diseases like obesity-induced chronic inflammation could provide new therapeutic directions for expanding its clinical applications.

Future research should focus on leveraging multi-omics and artificial intelligence to predict TBK1's behavior in various diseases. For example, identifying genes that can collaborate with TBK1 in the repair of TACSTD2 mutations or predicting TBK1's involvement in cancer response to ADC therapies could become key strategies for precision medicine.

In conclusion, TBK1 is a critical player in immune response, neurodegeneration, and cancer progression, offering potential therapeutic opportunities. However, careful modulation of TBK1 activity, considering its broad biological effects, will be essential for maximizing its clinical benefits across multiple disease areas.

Reference

Runde AP, Mack R, S J PB, et al. The role of TBK1 in cancer pathogenesis and anticancer immunity. J Exp Clin Cancer Res. 2022 Apr 9;41(1):135.
Hu L, Zhang Q. Mechanism of TBK1 activation in cancer cells. Cell Insight. 2024 Aug 22;3(5):100197.

Quick Inquiry

Interested in learning more?

Contact us today for a free consultation with the scientific team and discover how Creative Biogene can be a valuable resource and partner for your organization.

Request a quote today!

Inquiry