TANK-binding kinase 1 explained

TBK1 (TANK-binding kinase 1) is an enzyme with kinase activity. Specifically, it is a serine / threonine protein kinase.^[1] It is encoded by the TBK1 gene in humans.^[2] This kinase is mainly known for its role in innate immunity antiviral response. However, TBK1 also regulates cell proliferation, apoptosis, autophagy, and anti-tumor immunity. Insufficient regulation of TBK1 activity leads to autoimmune, neurodegenerative diseases or tumorigenesis.^{[3] [4]}

Structure and regulation of activity

TBK1 is a non-canonical IKK kinase that phosphorylates the nuclear factor kB (NFkB). It shares sequence homology with canonical IKK.

The N-terminus of the protein contains the kinase domain (region 9-309) and the ubiquitin-like domain (region 310-385). The C-terminus is formed by two coiled-coil structures (region 407-713) that provide a surface for homodimerization.

The autophosphorylation of serine 172, which requires homodimerization and ubiquitinylation of lysines 30 and 401, is necessary for kinase activity.^[5]

Involvement in signaling pathways

TBK1 is involved in many signaling pathways and forms a node between them. For this reason, regulation of its involvement in individual signaling pathways is necessary. This is provided by adaptor proteins that interact with the dimerization domain of TBK1 to determine its location and access to substrates. Binding to TANK leads to localization to the perinuclear region and phosphorylation of substrates which is required for subsequent production of type I interferons (IFN-I). In contrast, binding to NAP1 and SINTBAD leads to localization in the cytoplasm and involvement in autophagy. Another adaptor protein that determines the location of TBK1 is TAPE. TAPE targets TBK1 to endolysosomes.

A key interest in TBK1 is due to its role in innate immunity, especially in antiviral responses. TBK1 is redundant with IKK

\epsilon , but TBK1 seems to play a more important role. After triggering antiviral signaling through PRRs (pattern recognition receptors), TBK1 is activated. Subsequently, it phosphorylates the transcription factor IRF3, which is translocated to the nucleus, and promotes production of IFN-I.

As a non-canonical IKK, TBK1 is also involved in the non-canonical NFkB pathway. It phosphorylates p100/NF-κB2, which is subsequently processed in the proteasome and released as a p52 subunit. This subunit dimerizes with RelB and mediates gene expression.^[6]

In the canonical NFkB pathway, 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.

TBK1 promotes autophagy involved in pathogen and mitochondrial clearance.^[7] TBK1 phosphorylates autophagy receptors ^{[8] [9]} and components of the autophagy apparatus.^{[10] [11]} Furthermore, TBK1 is also involved in the regulation of cell proliferation, apoptosis and glucose metabolism.

Interactions

TANK-binding kinase 1 has been shown to interact with:

• NCK1,^[12]
• TANK,^[13]
• TRAF2^{[14] [15]} and
• TBKBP1 aka SINTBAD^[16]

Transcription factors activated upon TBK1 activation include IRF3, IRF7^[17] and ZEB1.^[18]

Clinical significance

Deregulation of TBK1 activity and mutations in this protein are associated with many diseases. Due to the role of TBK1 in cell survival, deregulation of its activity is associated with tumorogenesis. There are also many autoimmune (e.g., rheumatoid arthritis, sympathetic lupus), neurodegenerative (e.g., amyotrophic lateral sclerosis), and infantile (e.g., herpesviral encephalitis) diseases.

The loss of TBK1 cause embryonic lethality in mice.

Inhibition of IκB kinase (IKK) and IKK-related kinases, IKBKE (IKKε) and TANK-binding kinase 1 (TBK1), has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer,^[19] and a way to overcome resistance to cancer immunotherapy.^[20]

See also

• CGAS–STING cytosolic DNA sensing pathway

Further reading

• Chou MM, Hanafusa H . A novel ligand for SH3 domains. The Nck adaptor protein binds to a serine/threonine kinase via an SH3 domain . The Journal of Biological Chemistry . 270 . 13 . 7359–7364 . March 1995 . 7706279 . 10.1074/jbc.270.13.7359 . free .
• Chen ZJ, Parent L, Maniatis T . Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity . Cell . 84 . 6 . 853–862 . March 1996 . 8601309 . 10.1016/S0092-8674(00)81064-8 . 112412 . free .
• Zandi E, Chen Y, Karin M . Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: discrimination between free and NF-kappaB-bound substrate . Science . 281 . 5381 . 1360–1363 . August 1998 . 9721103 . 10.1126/science.281.5381.1360 .
• Bonnard M, Mirtsos C, Suzuki S, Graham K, Huang J, Ng M, Itié A, Wakeham A, Shahinian A, Henzel WJ, Elia AJ, Shillinglaw W, Mak TW, Cao Z, Yeh WC . 6 . Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription . The EMBO Journal . 19 . 18 . 4976–4985 . September 2000 . 10990461 . 314216 . 10.1093/emboj/19.18.4976 .
• Kishore N, Huynh QK, Mathialagan S, Hall T, Rouw S, Creely D, Lange G, Caroll J, Reitz B, Donnelly A, Boddupalli H, Combs RG, Kretzmer K, Tripp CS . 6 . IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme IKK-2: comparative analysis of recombinant human IKK-i, TBK-1, and IKK-2 . The Journal of Biological Chemistry . 277 . 16 . 13840–13847 . April 2002 . 11839743 . 10.1074/jbc.M110474200 . free .
• Chariot A, Leonardi A, Muller J, Bonif M, Brown K, Siebenlist U . Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases . The Journal of Biological Chemistry . 277 . 40 . 37029–37036 . October 2002 . 12133833 . 10.1074/jbc.M205069200 . free .
• Li SF, Fujita F, Hirai M, Lu R, Niida H, Nakanishi M . Genomic structure and characterization of the promoter region of the human NAK gene . Gene . 304 . 57–64 . January 2003 . 12568715 . 10.1016/S0378-1119(02)01179-4 .
• Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis T . 6 . IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway . Nature Immunology . 4 . 5 . 491–496 . May 2003 . 12692549 . 10.1038/ni921 . 19867234 .
• Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J . Triggering the interferon antiviral response through an IKK-related pathway . Science . 300 . 5622 . 1148–1151 . May 2003 . 12702806 . 10.1126/science.1081315 . 42641584 . 2003Sci...300.1148S .
• Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y, Doi T, Shimotohno K, Harada T, Nishida E, Hayashi H, Sugano S . 6 . Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways . Oncogene . 22 . 21 . 3307–3318 . May 2003 . 12761501 . 10.1038/sj.onc.1206406 . free .
• Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K, Akira S . Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling . Journal of Immunology . 171 . 8 . 4304–4310 . October 2003 . 14530355 . 10.4049/jimmunol.171.8.4304 . free .
• Fujita F, Taniguchi Y, Kato T, Narita Y, Furuya A, Ogawa T, Sakurai H, Joh T, Itoh M, Delhase M, Karin M, Nakanishi M . 6 . Identification of NAP1, a regulatory subunit of IkappaB kinase-related kinases that potentiates NF-kappaB signaling . Molecular and Cellular Biology . 23 . 21 . 7780–7793 . November 2003 . 14560022 . 207563 . 10.1128/MCB.23.21.7780-7793.2003 .
• Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G . 6 . A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway . Nature Cell Biology . 6 . 2 . 97–105 . February 2004 . 14743216 . 10.1038/ncb1086 . 11683986 .
• tenOever BR, Sharma S, Zou W, Sun Q, Grandvaux N, Julkunen I, Hemmi H, Yamamoto M, Akira S, Yeh WC, Lin R, Hiscott J . 6 . Activation of TBK1 and IKKvarepsilon kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunity . Journal of Virology . 78 . 19 . 10636–10649 . October 2004 . 15367631 . 516426 . 10.1128/JVI.78.19.10636-10649.2004 .
• Kuai J, Wooters J, Hall JP, Rao VR, Nickbarg E, Li B, Chatterjee-Kishore M, Qiu Y, Lin LL . 6 . NAK is recruited to the TNFR1 complex in a TNFalpha-dependent manner and mediates the production of RANTES: identification of endogenous TNFR-interacting proteins by a proteomic approach . The Journal of Biological Chemistry . 279 . 51 . 53266–53271 . December 2004 . 15485837 . 10.1074/jbc.M411037200 . free .
• Buss H, Dörrie A, Schmitz ML, Hoffmann E, Resch K, Kracht M . Constitutive and interleukin-1-inducible phosphorylation of p65 NF-κB at serine 536 is mediated by multiple protein kinases including IκB kinase IKK-α, IKK-β, IKK-ε, TRAF family member-associated (TANK)-binding kinase 1 (TBK1), and an unknown kinase and couples p65 to TATA-binding protein-associated factor II31-mediated interleukin-8 transcription . The Journal of Biological Chemistry . 279 . 53 . 55633–55643 . December 2004 . 15489227 . 10.1074/jbc.M409825200 . free .

Notes and References

1. Helgason E, Phung QT, Dueber EC . Recent insights into the complexity of Tank-binding kinase 1 signaling networks: the emerging role of cellular localization in the activation and substrate specificity of TBK1 . FEBS Letters . 587 . 8 . 1230–1237 . April 2013 . 23395801 . 10.1016/j.febslet.2013.01.059 . free .
2. Web site: Entrez Gene: TBK1 TANK-binding kinase 1.
3. Louis C, Burns C, Wicks I . TANK-Binding Kinase 1-Dependent Responses in Health and Autoimmunity . Frontiers in Immunology . 9 . 434 . 2018-03-06 . 29559975 . 5845716 . 10.3389/fimmu.2018.00434 . free .
4. Cruz VH, Brekken RA . Assessment of TANK-binding kinase 1 as a therapeutic target in cancer . Journal of Cell Communication and Signaling . 12 . 1 . 83–90 . March 2018 . 29218456 . 5842199 . 10.1007/s12079-017-0438-y .
5. Oakes JA, Davies MC, Collins MO . TBK1: a new player in ALS linking autophagy and neuroinflammation . Molecular Brain . 10 . 1 . 5 . February 2017 . 28148298 . 5288885 . 10.1186/s13041-017-0287-x . free .
6. Durand JK, Zhang Q, Baldwin AS . Roles for the IKK-Related Kinases TBK1 and IKKε in Cancer . Cells . 7 . 9 . 139 . September 2018 . 30223576 . 6162516 . 10.3390/cells7090139 . free .
7. von Muhlinen N, Thurston T, Ryzhakov G, Bloor S, Randow F . NDP52, a novel autophagy receptor for ubiquitin-decorated cytosolic bacteria . Autophagy . 6 . 2 . 288–289 . February 2010 . 20104023 . 10.4161/auto.6.2.11118 . 1059428 . free .
8. Pilli M, Arko-Mensah J, Ponpuak M, Roberts E, Master S, Mandell MA, Dupont N, Ornatowski W, Jiang S, Bradfute SB, Bruun JA, Hansen TE, Johansen T, Deretic V . 6 . TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation . Immunity . 37 . 2 . 223–234 . August 2012 . 22921120 . 3428731 . 10.1016/j.immuni.2012.04.015 .
9. Richter B, Sliter DA, Herhaus L, Stolz A, Wang C, Beli P, Zaffagnini G, Wild P, Martens S, Wagner SA, Youle RJ, Dikic I . 6 . Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria . Proceedings of the National Academy of Sciences of the United States of America . 113 . 15 . 4039–4044 . April 2016 . 27035970 . 4839414 . 10.1073/pnas.1523926113 . free . 2016PNAS..113.4039R .
10. Kumar S, Gu Y, Abudu YP, Bruun JA, Jain A, Farzam F, Mudd M, Anonsen JH, Rusten TE, Kasof G, Ktistakis N, Lidke KA, Johansen T, Deretic V . 6 . Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation . Developmental Cell . 49 . 1 . 130–144.e6 . April 2019 . 30827897 . 6907693 . 10.1016/j.devcel.2019.01.027 .
11. Herhaus L, Bhaskara RM, Lystad AH, Gestal-Mato U, Covarrubias-Pinto A, Bonn F, Simonsen A, Hummer G, Dikic I . 6 . TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls autophagosome shedding by ATG4 protease . EMBO Reports . 21 . 1 . e48317 . January 2020 . 31709703 . 6945063 . 10.15252/embr.201948317 .
12. Chou MM, Hanafusa H . A novel ligand for SH3 domains. The Nck adaptor protein binds to a serine/threonine kinase via an SH3 domain . The Journal of Biological Chemistry . 270 . 13 . 7359–7364 . March 1995 . 7706279 . 10.1074/jbc.270.13.7359 . free .
13. Pomerantz JL, Baltimore D . NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase . The EMBO Journal . 18 . 23 . 6694–6704 . December 1999 . 10581243 . 1171732 . 10.1093/emboj/18.23.6694 .
14. Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G . 6 . A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway . Nature Cell Biology . 6 . 2 . 97–105 . February 2004 . 14743216 . 10.1038/ncb1086 . 11683986 .
15. Bonnard M, Mirtsos C, Suzuki S, Graham K, Huang J, Ng M, Itié A, Wakeham A, Shahinian A, Henzel WJ, Elia AJ, Shillinglaw W, Mak TW, Cao Z, Yeh WC . 6 . Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription . The EMBO Journal . 19 . 18 . 4976–4985 . September 2000 . 10990461 . 314216 . 10.1093/emboj/19.18.4976 .
16. Web site: TANK-binding kinase 1-binding protein 1. UniProt. 30 Jun 2018.
17. Ikeda F, Hecker CM, Rozenknop A, Nordmeier RD, Rogov V, Hofmann K, Akira S, Dötsch V, Dikic I . 6 . Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes . The EMBO Journal . 26 . 14 . 3451–3462 . July 2007 . 17599067 . 1933404 . 10.1038/sj.emboj.7601773 .
18. Liu W, Huang YJ, Liu C, Yang YY, Liu H, Cui JG, Cheng Y, Gao F, Cai JM, Li BL . 6 . Inhibition of TBK1 attenuates radiation-induced epithelial-mesenchymal transition of A549 human lung cancer cells via activation of GSK-3β and repression of ZEB1 . Laboratory Investigation; A Journal of Technical Methods and Pathology . 94 . 4 . 362–370 . April 2014 . 24468793 . 10.1038/labinvest.2013.153 . free .
19. Llona-Minguez S, Baiget J, Mackay SP . Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases . Pharmaceutical Patent Analyst . 2 . 4 . 481–498 . July 2013 . 24237125 . 10.4155/ppa.13.31 .
20. Y.. Sun. S.. Anderson. Targeting TBK1 to overcome resistance to cancer immunotherapy. January 12, 2023. Nature. 615 . 7950 . 158–167 . 10.1038/s41586-023-05704-6. 36634707. 10171827. 2023Natur.615..158S .