TBK1

GeneName

TBK1

Summary

TBK1, also known as TANK binding kinase 1, NAK, or TBK-1, is an 84 kDa serine/threonine protein kinase that is predominantly localised in the cytoplasm and associated with various intracellular membrane-bounded organelles. It plays a pivotal role in the activation of the innate immune response, particularly in antiviral defence mechanisms. TBK1 is involved in several key biological processes, including the canonical NF-kappaB signal transduction pathway and the cGAS/STING signalling pathway, which are crucial for the detection and response to viral infections. Additionally, TBK1 is implicated in macroautophagy and the regulation of interferon production, highlighting its importance in immune regulation and cellular homeostasis.

Importance

TBK1 is relevant to: - The innate immune response, especially in the context of viral infections, due to its role in activating antiviral pathways. - Inflammatory diseases, as it regulates the inflammatory response and is involved in the signalling pathways of toll-like receptors. - Cancer research, given its involvement in NF-kappaB signalling, which is often dysregulated in tumours. - Autophagy and cellular stress responses, as it contributes to the positive regulation of macroautophagy and xenophagy, processes important for cellular quality control and pathogen elimination.

Top Products

For researchers investigating TBK1, we highly recommend the top-selling recombinant antibody, Anti-NAK/TBK1 antibody [EP611Y] (ab40676). This antibody has been validated in knockout models, ensuring its reliability in various applications, including Western blotting (WB), immunocytochemistry (ICC), and immunohistochemistry (IHC). With 158 citations, it is well-regarded in the research community, making it an excellent choice for those seeking dependable TBK1 detection in their studies.

Abcam Product Citation Summary

The data indicates that TBK1 is frequently studied in the context of viral infections and immune response mechanisms, particularly in human cell lines such as HeLa and HEK293T. The use of various applications, including Western blotting and immunofluorescence, highlights the importance of TBK1 in understanding cellular responses to viral stimuli and its role in mitophagy and immune signalling pathways.

Abcam Product Citation Table

Domain

Comprises A N-terminal kinase domain, a ubiquitin-like domain and a C-terminal coiled-coil region mediating homodimerization.

Function

Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents (PubMed:10581243, PubMed:11839743, PubMed:12692549, PubMed:12702806, PubMed:14703513, PubMed:15367631, PubMed:15485837, PubMed:18583960, PubMed:21138416, PubMed:23453971, PubMed:23453972, PubMed:23746807, PubMed:25636800, PubMed:26611359, PubMed:32404352, PubMed:34363755). Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X (PubMed:12692549, PubMed:12702806, PubMed:14703513, PubMed:15367631, PubMed:18583960, PubMed:25636800). This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB (PubMed:12702806, PubMed:15367631, PubMed:25636800, PubMed:32972995). In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli (PubMed:23453971, PubMed:23453972, PubMed:23746807). Plays a key role in IRF3 activation: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 (PubMed:25636800, PubMed:30842653). Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce expression of interferons (PubMed:25636800). Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes (PubMed:21931631). Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus (PubMed:10783893, PubMed:15489227). Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy (PubMed:21617041). Phosphorylates SMCR8 component of the C9orf72-SMCR8 complex, promoting autophagosome maturation (PubMed:27103069). Phosphorylates ATG8 proteins MAP1LC3C and GABARAPL2, thereby preventing their delipidation and premature removal from nascent autophagosomes (PubMed:31709703). Phosphorylates and activates AKT1 (PubMed:21464307). Seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity (By similarity). Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C (PubMed:21270402). Phosphorylates Borna disease virus (BDV) P protein (PubMed:16155125). Plays an essential role in the TLR3- and IFN-dependent control of herpes virus HSV-1 and HSV-2 infections in the central nervous system (PubMed:22851595). Acts both as a positive and negative regulator of the mTORC1 complex, depending on the context: activates mTORC1 in response to growth factors by catalyzing phosphorylation of MTOR, while it limits the mTORC1 complex by promoting phosphorylation of RPTOR (PubMed:29150432, PubMed:31530866). Involved in the regulation of TNF-induced RIPK1-mediated cell death, probably acting via CYLD phosphorylation that in turn controls RIPK1 ubiquitination status (PubMed:34363755). Participates also in the differentiation of T follicular regulatory cells together with the receptor ICOS (PubMed:27135603).

Involvement in disease

Glaucoma 1, open angle, P

GLC1P

A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. GLC1P is characterized by early onset, thin central corneas and low intraocular pressure.

None

The disease may be caused by variants affecting the gene represented in this entry. A copy number variation on chromosome 12q14 consisting of a 300 kb duplication that includes TBK1, XPOT, RASSF3 and GNS has been found in individuals affected by glaucoma. TBK1 is the most likely candidate for the disorder (PubMed:21447600).

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4

FTDALS4

A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis.

None

The disease is caused by variants affecting the gene represented in this entry.

Encephalopathy, acute, infection-induced, 8, herpes-specific

IIAE8

A rare, often fatal complication of herpes simplex infection, caused by virus spreading in the central nervous system. Disease manifestations include low-grade fever, severe headache, nausea, vomiting, and lethargy. Neurological features include confusion, acute memory disturbances, disorientation, behavioral changes, hemiparesis and seizures.

None

Disease susceptibility is associated with variants affecting the gene represented in this entry.

Autoinflammation with arthritis and vasculitis

AIARV

An autosomal recessive disorder characterized by onset of chronic and systemic autoinflammation in infancy or early childhood. Affected individuals have recurrent fever, erythematous skin rashes, vasculitis, oral aphthous lesions, and polyarthritis. Additional variable features are poor overall growth, microcytic anemia, mild intellectual disability, and seizures.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

Autophosphorylation at Ser-172 activates the kinase, and is an essential step for virus-triggered signaling. Phosphorylated by IKBKB/IKKB at Ser-172. Phosphorylation requires homodimerization and ubiquitination at Lys-30 and Lys-401. Dephosphorylated at Ser-172 by PPM1B and this negatively regulates its role in mediating antiviral response.

'Lys-63'-linked polyubiquitination by MIB1 after RNA virus infection, or by NRDP1 after LPS stimulation at Lys-30 and Lys-401, participates in kinase activation. 'Lys-48'-linked polyubiquitination at Lys-670 by DTX4 leads to proteasomal degradation. 'Lys-48'-linked polyubiquitination by TRAIP also leads to proteasomal degradation. 'Lys-48'-linked polyubiquitination by TRAF7; leading to proteasomal degradation (PubMed:37086853). 'Lys-63'-linked polyubiquitination by RNF128 at Lys-30 and Lys-401 leads to the activation of antiviral responses. 'Lys-48'-linked polyubiquitination after 'lys-33'-linked deubiquitination by USP38 promotes TBK1 degradation (PubMed:27692986).

(Microbial infection) Interaction with SARS-CoV-2 M protein induces 'Lys-48'-linked ubiquitination which leads to proteasomal degradation.

(Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1 on both 'Lys-48' and 'Lys-63'-linked ubiquitin chains; leading to inhibition of type I interfewron production.

Sequence Similarities

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily.

Tissue Specificity

Ubiquitous with higher expression in testis. Expressed in the ganglion cells, nerve fiber layer and microvasculature of the retina.

Cellular localization

• Cytoplasm
• Upon mitogen stimulation or triggering of the immune system, TBK1 is recruited to the exocyst by EXOC2.

Alternative names

NAK, TBK1, Serine/threonine-protein kinase TBK1, NF-kappa-B-activating kinase, T2K, TANK-binding kinase 1

Database links

swissprot:Q9UHD2 entrezGene:29110 omim:604834

Other research areas

• Epigenetics
• Neuroscience