TANK-binding kinase 1

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.{{cite journal | vauthors = Oakes JA, Davies MC, Collins MO | title = TBK1: a new player in ALS linking autophagy and neuroinflammation | journal = Molecular Brain | volume = 10 | issue = 1 | pages = 5 | date = February 2017 | pmid = 28148298 | pmc = 5288885 | doi = 10.1186/s13041-017-0287-x | doi-access = free }}

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$\backslash epsilon$, 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 IκB kinases (IKK), TBK1 is also involved in the non-canonical NF-κB 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.{{cite journal | vauthors = Durand JK, Zhang Q, Baldwin AS | title = Roles for the IKK-Related Kinases TBK1 and IKKε in Cancer | journal = Cells | volume = 7 | issue = 9 | pages = 139 | date = September 2018 | pmid = 30223576 | pmc = 6162516 | doi = 10.3390/cells7090139 | doi-access = free }}

In the canonical NF-κB pathway, the NF-kappa-B (NF-κB) complex of proteins is inhibited by I-kappa-B (IκB) proteins, which inactivate NF-κB by trapping it in the cytoplasm. Phosphorylation of serine residues on the IκB proteins by IκB kinases (IKK) marks them for destruction via the ubiquitination pathway, thereby allowing activation and nuclear translocation of the NF-κB complex. The protein encoded by this gene is similar to IκB kinases and can mediate NF-κB activation in response to certain growth factors.

TBK1 promotes autophagy involved in pathogen and mitochondrial clearance.{{cite journal | vauthors = von Muhlinen N, Thurston T, Ryzhakov G, Bloor S, Randow F | title = NDP52, a novel autophagy receptor for ubiquitin-decorated cytosolic bacteria | journal = Autophagy | volume = 6 | issue = 2 | pages = 288–289 | date = February 2010 | pmid = 20104023 | doi = 10.4161/auto.6.2.11118 | s2cid = 1059428 | doi-access = free }} TBK1 phosphorylates autophagy receptors {{cite journal | vauthors = 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 | title = TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation | journal = Immunity | volume = 37 | issue = 2 | pages = 223–234 | date = August 2012 | pmid = 22921120 | pmc = 3428731 | doi = 10.1016/j.immuni.2012.04.015 }}{{cite journal | vauthors = Richter B, Sliter DA, Herhaus L, Stolz A, Wang C, Beli P, Zaffagnini G, Wild P, Martens S, Wagner SA, Youle RJ, Dikic I | title = Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 15 | pages = 4039–4044 | date = April 2016 | pmid = 27035970 | pmc = 4839414 | doi = 10.1073/pnas.1523926113 | doi-access = free | bibcode = 2016PNAS..113.4039R }} and components of the autophagy apparatus.{{cite journal | vauthors = 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 | title = Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation | journal = Developmental Cell | volume = 49 | issue = 1 | pages = 130–144.e6 | date = April 2019 | pmid = 30827897 | pmc = 6907693 | doi = 10.1016/j.devcel.2019.01.027 }}{{cite journal | vauthors = Herhaus L, Bhaskara RM, Lystad AH, Gestal-Mato U, Covarrubias-Pinto A, Bonn F, Simonsen A, Hummer G, Dikic I | title = TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls autophagosome shedding by ATG4 protease | journal = EMBO Reports | volume = 21 | issue = 1 | pages = e48317 | date = January 2020 | pmid = 31709703 | pmc = 6945063 | doi = 10.15252/embr.201948317 }} Furthermore, TBK1 is also involved in the regulation of cell proliferation, apoptosis and glucose metabolism.

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

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• NCK1,{{cite journal | vauthors = Chou MM, Hanafusa H | title = A novel ligand for SH3 domains. The Nck adaptor protein binds to a serine/threonine kinase via an SH3 domain | journal = The Journal of Biological Chemistry | volume = 270 | issue = 13 | pages = 7359–7364 | date = March 1995 | pmid = 7706279 | doi = 10.1074/jbc.270.13.7359 | doi-access = free }}
• TANK,{{cite journal | vauthors = Pomerantz JL, Baltimore D | title = NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase | journal = The EMBO Journal | volume = 18 | issue = 23 | pages = 6694–6704 | date = December 1999 | pmid = 10581243 | pmc = 1171732 | doi = 10.1093/emboj/18.23.6694 }}
• TRAF2{{cite journal | vauthors = 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 | title = A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway | journal = Nature Cell Biology | volume = 6 | issue = 2 | pages = 97–105 | date = February 2004 | pmid = 14743216 | doi = 10.1038/ncb1086 | s2cid = 11683986 }}{{cite journal | vauthors = 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 | title = Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription | journal = The EMBO Journal | volume = 19 | issue = 18 | pages = 4976–4985 | date = September 2000 | pmid = 10990461 | pmc = 314216 | doi = 10.1093/emboj/19.18.4976 }} and
• TBKBP1 aka SINTBAD{{cite web| title=TANK-binding kinase 1-binding protein 1| website=UniProt| access-date=30 Jun 2018| url=https://www.uniprot.org/uniprot/A7MCY6}}

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Transcription factors activated upon TBK1 activation include IRF3, IRF7{{cite journal | vauthors = Ikeda F, Hecker CM, Rozenknop A, Nordmeier RD, Rogov V, Hofmann K, Akira S, Dötsch V, Dikic I | title = Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes | journal = The EMBO Journal | volume = 26 | issue = 14 | pages = 3451–3462 | date = July 2007 | pmid = 17599067 | pmc = 1933404 | doi = 10.1038/sj.emboj.7601773 }} and ZEB1.

{{cite journal | vauthors = Liu W, Huang YJ, Liu C, Yang YY, Liu H, Cui JG, Cheng Y, Gao F, Cai JM, Li BL | title = Inhibition of TBK1 attenuates radiation-induced epithelial-mesenchymal transition of A549 human lung cancer cells via activation of GSK-3β and repression of ZEB1 | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 94 | issue = 4 | pages = 362–370 | date = April 2014 | pmid = 24468793 | doi = 10.1038/labinvest.2013.153 | doi-access = free }}

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,{{cite journal | vauthors = Llona-Minguez S, Baiget J, Mackay SP | title = Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases | journal = Pharmaceutical Patent Analyst | volume = 2 | issue = 4 | pages = 481–498 | date = July 2013 | pmid = 24237125 | doi = 10.4155/ppa.13.31 }} and a way to overcome resistance to cancer immunotherapy.{{cite journal | vauthors = Sun Y, Revach OY, Anderson S, Kessler EA, Wolfe CH, Jenney A, Mills CE, Robitschek EJ, Davis TG, Kim S, Fu A, Ma X, Gwee J, Tiwari P, Du PP, Sindurakar P, Tian J, Mehta A, Schneider AM, Yizhak K, Sade-Feldman M, LaSalle T, Sharova T, Xie H, Liu S, Michaud WA, Saad-Beretta R, Yates KB, Iracheta-Vellve A, Spetz JK, Qin X, Sarosiek KA, Zhang G, Kim JW, Su MY, Cicerchia AM, Rasmussen MQ, Klempner SJ, Juric D, Pai SI, Miller DM, Giobbie-Hurder A, Chen JH, Pelka K, Frederick DT, Stinson S, Ivanova E, Aref AR, Paweletz CP, Barbie DA, Sen DR, Fisher DE, Corcoran RB, Hacohen N, Sorger PK, Flaherty KT, Boland GM, Manguso RT, Jenkins RW | title = Targeting TBK1 to overcome resistance to cancer immunotherapy | journal = Nature | volume = 615 | issue = 7950 | pages = 158–167 | date = March 2023 | pmid = 36634707 | pmc = 10171827 | doi = 10.1038/s41586-023-05704-6 | bibcode = 2023Natur.615..158S }}

• CGAS–STING cytosolic DNA sensing pathway

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{{Refend}}

{{Serine/threonine-specific protein kinases}}

{{Enzymes}}

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Category:EC 2.7.11