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{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
{{Infobox_gene}}
'''TBK1 (TANK-binding kinase 1)''' is an [[enzyme]] with [[kinase]] activity. Specifically, it is a [[serine]] / [[threonine]] protein kinase.<ref name=":0">{{cite journal | vauthors = Helgason E, Phung QT, Dueber EC | title = 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 | journal = FEBS Letters | volume = 587 | issue = 8 | pages = 1230–1237 | date = April 2013 | pmid = 23395801 | doi = 10.1016/j.febslet.2013.01.059 | doi-access = free }}</ref> It is encoded by the TBK1 [[gene]] in humans.<ref name="entrez">{{Cite web|url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=29110|title=Entrez Gene: TBK1 TANK-binding kinase 1}}</ref> This kinase is mainly known for its role in [[Innate immune system|innate immunity]] antiviral response. However, TBK1 also regulates [[cell proliferation]], [[apoptosis]], [[autophagy]], and anti-[[tumor]] immunity.<ref name=":0" /> Insufficient regulation of TBK1 activity leads to [[Autoimmunity|autoimmune]], [[Neurodegeneration|neurodegenerative]] diseases or [[Carcinogenesis|tumorigenesis]].<ref name=":1">{{cite journal | vauthors = Louis C, Burns C, Wicks I | title = TANK-Binding Kinase 1-Dependent Responses in Health and Autoimmunity | journal = Frontiers in Immunology | volume = 9 | pages = 434 | date = 2018-03-06 | pmid = 29559975 | pmc = 5845716 | doi = 10.3389/fimmu.2018.00434 | doi-access = free }}</ref><ref name=":3">{{cite journal | vauthors = Cruz VH, Brekken RA | title = Assessment of TANK-binding kinase 1 as a therapeutic target in cancer | journal = Journal of Cell Communication and Signaling | volume = 12 | issue = 1 | pages = 83–90 | date = March 2018 | pmid = 29218456 | pmc = 5842199 | doi = 10.1007/s12079-017-0438-y }}</ref>
'''Serine/threonine-protein kinase TBK1''' is an [[enzyme]] that in humans is encoded by the ''TBK1'' [[gene]].<ref name="pmid10581243">{{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 = EMBO J | volume = 18 | issue = 23 | pages = 6694–704 |date=January 2000 | pmid = 10581243 | pmc = 1171732 | doi = 10.1093/emboj/18.23.6694 }}</ref><ref name="pmid10783893">{{cite journal |vauthors=Tojima Y, Fujimoto A, Delhase M, Chen Y, Hatakeyama S, Nakayama K, Kaneko Y, Nimura Y, Motoyama N, Ikeda K, Karin M, Nakanishi M | title = NAK is an IkappaB kinase-activating kinase | journal = Nature | volume = 404 | issue = 6779 | pages = 778–82 |date=May 2000 | pmid = 10783893 | pmc = | doi = 10.1038/35008109 }}</ref><ref name="entrez">{{Cite web| title = Entrez Gene: TBK1 TANK-binding kinase 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=29110| accessdate = }}</ref>


== Structure and regulation of activity ==
<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
TBK1 is a non-canonical IKK kinase that [[Phosphorylation|phosphorylates]] the nuclear factor kB (NFkB). It shares [[sequence homology]] with canonical IKK.<ref name=":0" />
{{PBB_Summary
| section_title =
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| summary_text = The NF-kappa-B ([[NFKB]]) complex of proteins is inhibited by I-kappa-B ([[NF-κB#Inhibition|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 factor]]s. For example, the protein can form a complex with the IKB protein [[TANK (gene)|TANK]] and [[TRAF2]] and release the NFKB inhibition caused by TANK.<ref name="entrez"/>
}}


The [[N-terminus]] of the protein contains the [[Protein kinase domain|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 [[Protein dimer|homodimerization]].<ref name=":0" /><ref name="entrez" />
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==Interactions==

The [[autophosphorylation]] of [[serine]] 172, which requires homodimerization and ubiquitinylation of [[lysine]]s 30 and 401, is necessary for kinase activity.<ref name=":4">{{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 }}</ref>

== 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 [[Signal transducing adaptor protein|adaptor proteins]] that interact with the dimerization domain of TBK1 to determine its location and access to [[Substrate (biochemistry)|substrates]]. Binding to TANK leads to localization to the [[Nuclear envelope|perinuclear region]] and phosphorylation of substrates which is required for subsequent production of type I [[interferon]]s (IFN-I). In contrast, binding to [[AZI2|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 [[endolysosome]]s.<ref name=":0" />

A key interest in TBK1 is due to its role in [[Innate immune system|innate immunity]], especially in antiviral responses. TBK1 is redundant with [[IκB kinase|IKK]]<math>\epsilon</math>, but TBK1 seems to play a more important role. After triggering antiviral signaling through PRRs ([[pattern recognition receptor]]s), TBK1 is activated. Subsequently, it phosphorylates the transcription factor [[IRF3]], which is translocated to the [[Cell nucleus|nucleus]], and promotes production of IFN-I.<ref name=":1" />

As a non-canonical IκB kinases (IKK), TBK1 is also involved in the non-canonical [[NF-κB]] pathway. It phosphorylates [[NFKB2|p100/NF-κB2]], which is subsequently processed in the [[proteasome]] and released as a [[NFKB2|p52]] subunit. This subunit [[Dimer (chemistry)|dimerizes]] with RelB and mediates [[gene expression]].<ref name=":2">{{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 }}</ref>

⚫
In the canonical NF-κB pathway, the NF-kappa-B (NF-κB) complex of proteins is inhibited by I-kappa-B ([[NF-κB#Inhibition|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 factor]]s.<ref name="entrez" />

TBK1 promotes [[autophagy]] involved in pathogen and [[Mitochondrion|mitochondrial]] clearance.<ref>{{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 }}</ref> TBK1 phosphorylates [[autophagy]] receptors <ref>{{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 | display-authors = 6 | 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 }}</ref><ref>{{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 | display-authors = 6 | 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 }}</ref> and components of the autophagy apparatus.<ref>{{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 | display-authors = 6 | 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 }}</ref><ref>{{cite journal | vauthors = Herhaus L, Bhaskara RM, Lystad AH, Gestal-Mato U, Covarrubias-Pinto A, Bonn F, Simonsen A, Hummer G, Dikic I | display-authors = 6 | 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 }}</ref> Furthermore, TBK1 is also involved in the regulation of [[cell proliferation]], [[apoptosis]] and [[glucose]] metabolism.<ref name=":2" />

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== Interactions ==
TANK-binding kinase 1 has been shown to [[Protein-protein interaction|interact]] with:
TANK-binding kinase 1 has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
{{div col|colwidth=20em}}
* [[NCK1]],<ref name = pmid7706279>{{cite journal | date = March 1995 |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 = J. Biol. Chem. | volume = 270 | issue = 13 | pages = 7359–64 | pmid = 7706279 | doi = 10.1074/jbc.270.13.7359}}</ref>
* [[NCK1]],<ref name = pmid7706279>{{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 }}</ref>
* [[TANK (gene)|TANK]],<ref name="pmid10581243">{{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 }}</ref><ref name = pmid14743216/>
* [[TANK (gene)|TANK]],<ref name = pmid10581243 /><ref name = pmid14743216/>
* [[TRAF2]]<ref name = pmid14743216>{{cite journal | date = February 2004 |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 = Nat. Cell Biol. | volume = 6 | issue = 2 | pages = 97–105 | pmid = 14743216 | doi = 10.1038/ncb1086}}</ref><ref name = pmid10990461>{{cite journal | date = September 2000 |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 = EMBO J. | volume = 19 | issue = 18 | pages = 4976–85 | pmid = 10990461 | pmc = 314216 | doi = 10.1093/emboj/19.18.4976}}</ref> and
* [[TRAF2]]<ref name = pmid14743216>{{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 | display-authors = 6 | 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 }}</ref><ref name = pmid10990461>{{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 | display-authors = 6 | 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 }}</ref> and
* [[TBKBP1]] aka SINTBAD<ref>{{cite web| title=TANK-binding kinase 1-binding protein 1| website=UniProt| access-date=30 Jun 2018| url=https://www.uniprot.org/uniprot/A7MCY6}}</ref>
* [[TBKBP1]] aka SINTBAD<ref>{{cite web| title=TANK-binding kinase 1-binding protein 1| website=UniProt| access-date=30 Jun 2018| url=https://www.uniprot.org/uniprot/A7MCY6}}</ref>
{{Div col end}}
{{Div col end}}


Transcriptional factors activated upon TBK1 activation include [[IRF3]], [[IRF7]] <ref name="pmid = 17599067">{{cite journal|date=Jun 2007|title=Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes.|journal=EMBO J.|volume=26|issue=14|pages=3451–3462|doi=10.1038/sj.emboj.7601773|pmc=1933404|pmid=17599067|author=Ikeda F}}</ref> and [[ZEB1]].
Transcription factors activated upon TBK1 activation include [[IRF3]], [[IRF7]]<ref name="pmid = 17599067">{{cite journal | vauthors = Ikeda F, Hecker CM, Rozenknop A, Nordmeier RD, Rogov V, Hofmann K, Akira S, Dötsch V, Dikic I | display-authors = 6 | 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 }}</ref> and [[ZEB1]].
<ref name=" pmid = 24468793">{{cite journal | author = Liu W | 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 = Lab. Invest. | volume = 94 | issue = 4 |date=Apr 2014 | pmid = 24468793 | url = http://www.nature.com/labinvest/journal/v94/n4/full/labinvest2013153a.html | pages = 362–370 | doi=10.1038/labinvest.2013.153}}</ref>
<ref name="pmid = 24468793">{{cite journal | vauthors = Liu W, Huang YJ, Liu C, Yang YY, Liu H, Cui JG, Cheng Y, Gao F, Cai JM, Li BL | display-authors = 6 | 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 }}</ref>


== Clinical significance ==
== Clinical significance ==
Deregulation of TBK1 activity and [[mutation]]s in this protein are associated with many diseases. Due to the role of TBK1 in [[cell survival]], deregulation of its activity is associated with [[Carcinogenesis|tumorogenesis]].<ref name=":3" /> There are also many [[autoimmune]] (e.g., [[rheumatoid arthritis]], sympathetic [[lupus]]), [[Neurodegeneration|neurodegenerative]] (e.g., [[amyotrophic lateral sclerosis]]), and infantile (e.g., [[herpesviral encephalitis]]) diseases.<ref name=":4" /><ref name=":1" />
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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.<ref name="pmid24237125">{{cite journal |vauthors=Llona-Minguez S, Baiget J, Mackay SP | title = Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases | journal = Pharm Pat Anal | volume = 2 | issue = 4 | pages = 481–98 | year = 2013 | pmid = 24237125 | doi = 10.4155/ppa.13.31 }}</ref>


The loss of TBK1 cause embryonic lethality in mice.<ref name="pmid = 17599067" />
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== See also==

⚫
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 [[Inflammation|inflammatory diseases]] and [[cancer]],<ref name="pmid24237125">{{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 }}</ref> and a way to overcome resistance to [[cancer immunotherapy]].<ref>{{cite journal|first1=Y.|last1=Sun|first2=S.|last2=Anderson|title=Targeting TBK1 to overcome resistance to cancer immunotherapy|date=January 12, 2023|journal=Nature|volume=615 |issue=7950 |pages=158–167 |doi=10.1038/s41586-023-05704-6|pmid=36634707|pmc=10171827|bibcode=2023Natur.615..158S }}</ref>

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== See also ==
* [[CGAS–STING cytosolic DNA sensing pathway]]
* [[CGAS–STING cytosolic DNA sensing pathway]]


==References==
== References ==
{{Reflist}}
{{Reflist}}


==Further reading==
== Further reading ==
{{Refbegin| 2}}
{{Refbegin| 2}}
*{{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=J. Biol. Chem. |volume=270 |issue= 13 |pages= 7359–64 |year= 1995 |pmid= 7706279 |doi= 10.1074/jbc.270.13.7359}}
* {{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 }}
*{{Cite journal |vauthors=Chen ZJ, Parent L, Maniatis T |title=Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity. |journal=Cell |volume=84 |issue= 6 |pages= 853–62 |year= 1996 |pmid= 8601309 |doi=10.1016/S0092-8674(00)81064-8 }}
* {{cite journal | vauthors = Chen ZJ, Parent L, Maniatis T | title = Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity | journal = Cell | volume = 84 | issue = 6 | pages = 853–862 | date = March 1996 | pmid = 8601309 | doi = 10.1016/S0092-8674(00)81064-8 | s2cid = 112412 | doi-access = free }}
*{{Cite journal |vauthors=Zandi E, Chen Y, Karin M |title=Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: discrimination between free and NF-kappaB-bound substrate. |journal=Science |volume=281 |issue= 5381 |pages= 1360–3 |year= 1998 |pmid= 9721103 |doi=10.1126/science.281.5381.1360 }}
* {{cite journal | vauthors = Zandi E, Chen Y, Karin M | title = Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: discrimination between free and NF-kappaB-bound substrate | journal = Science | volume = 281 | issue = 5381 | pages = 1360–1363 | date = August 1998 | pmid = 9721103 | doi = 10.1126/science.281.5381.1360 }}
*{{Cite journal |vauthors=Bonnard M, Mirtsos C, Suzuki S, etal |title=Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription. |journal=EMBO J. |volume=19 |issue= 18 |pages= 4976–85 |year= 2000 |pmid= 10990461 |doi= 10.1093/emboj/19.18.4976 | pmc=314216 }}
* {{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 | display-authors = 6 | 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 }}
*{{Cite journal |vauthors=Kishore N, Huynh QK, Mathialagan S, etal |title=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. |journal=J. Biol. Chem. |volume=277 |issue= 16 |pages= 13840–7 |year= 2002 |pmid= 11839743 |doi= 10.1074/jbc.M110474200 }}
* {{cite journal | vauthors = 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 | display-authors = 6 | title = 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 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 16 | pages = 13840–13847 | date = April 2002 | pmid = 11839743 | doi = 10.1074/jbc.M110474200 | doi-access = free }}
*{{Cite journal |vauthors=Chariot A, Leonardi A, Muller J, etal |title=Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases. |journal=J. Biol. Chem. |volume=277 |issue= 40 |pages= 37029–36 |year= 2002 |pmid= 12133833 |doi= 10.1074/jbc.M205069200 }}
* {{cite journal | vauthors = Chariot A, Leonardi A, Muller J, Bonif M, Brown K, Siebenlist U | title = Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases | journal = The Journal of Biological Chemistry | volume = 277 | issue = 40 | pages = 37029–37036 | date = October 2002 | pmid = 12133833 | doi = 10.1074/jbc.M205069200 | doi-access = free }}
*{{Cite journal |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 }}
* {{cite journal | vauthors = Li SF, Fujita F, Hirai M, Lu R, Niida H, Nakanishi M | title = Genomic structure and characterization of the promoter region of the human NAK gene | journal = Gene | volume = 304 | pages = 57–64 | date = January 2003 | pmid = 12568715 | doi = 10.1016/S0378-1119(02)01179-4 }}
*{{Cite journal |vauthors=Li SF, Fujita F, Hirai M, etal |title=Genomic structure and characterization of the promoter region of the human NAK gene. |journal=Gene |volume=304 |issue= |pages= 57–64 |year= 2003 |pmid= 12568715 |doi=10.1016/S0378-1119(02)01179-4 }}
* {{cite journal | vauthors = Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis T | display-authors = 6 | title = IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway | journal = Nature Immunology | volume = 4 | issue = 5 | pages = 491–496 | date = May 2003 | pmid = 12692549 | doi = 10.1038/ni921 | s2cid = 19867234 }}
*{{Cite journal |vauthors=Fitzgerald KA, McWhirter SM, Faia KL, etal |title=IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. |journal=Nat. Immunol. |volume=4 |issue= 5 |pages= 491–6 |year= 2003 |pmid= 12692549 |doi= 10.1038/ni921 }}
* {{cite journal | vauthors = Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J | title = Triggering the interferon antiviral response through an IKK-related pathway | journal = Science | volume = 300 | issue = 5622 | pages = 1148–1151 | date = May 2003 | pmid = 12702806 | doi = 10.1126/science.1081315 | s2cid = 42641584 | bibcode = 2003Sci...300.1148S }}
*{{Cite journal |vauthors=Sharma S, tenOever BR, Grandvaux N, etal |title=Triggering the interferon antiviral response through an IKK-related pathway. |journal=Science |volume=300 |issue= 5622 |pages= 1148–51 |year= 2003 |pmid= 12702806 |doi= 10.1126/science.1081315 }}
* {{cite journal | vauthors = Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y, Doi T, Shimotohno K, Harada T, Nishida E, Hayashi H, Sugano S | display-authors = 6 | title = Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways | journal = Oncogene | volume = 22 | issue = 21 | pages = 3307–3318 | date = May 2003 | pmid = 12761501 | doi = 10.1038/sj.onc.1206406 | doi-access = free }}
*{{Cite journal |vauthors=Matsuda A, Suzuki Y, Honda G, etal |title=Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways. |journal=Oncogene |volume=22 |issue= 21 |pages= 3307–18 |year= 2003 |pmid= 12761501 |doi= 10.1038/sj.onc.1206406 }}
* {{cite journal | vauthors = Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K, Akira S | title = 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 = Journal of Immunology | volume = 171 | issue = 8 | pages = 4304–4310 | date = October 2003 | pmid = 14530355 | doi = 10.4049/jimmunol.171.8.4304 | doi-access = free }}
*{{Cite journal |vauthors=Sato S, Sugiyama M, Yamamoto M, etal |title=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=J. Immunol. |volume=171 |issue= 8 |pages= 4304–10 |year= 2004 |pmid= 14530355 |doi= 10.4049/jimmunol.171.8.4304}}
* {{cite journal | vauthors = Fujita F, Taniguchi Y, Kato T, Narita Y, Furuya A, Ogawa T, Sakurai H, Joh T, Itoh M, Delhase M, Karin M, Nakanishi M | display-authors = 6 | title = Identification of NAP1, a regulatory subunit of IkappaB kinase-related kinases that potentiates NF-kappaB signaling | journal = Molecular and Cellular Biology | volume = 23 | issue = 21 | pages = 7780–7793 | date = November 2003 | pmid = 14560022 | pmc = 207563 | doi = 10.1128/MCB.23.21.7780-7793.2003 }}
* {{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 | display-authors = 6 | 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=Fujita F, Taniguchi Y, Kato T, etal |title=Identification of NAP1, a regulatory subunit of IkappaB kinase-related kinases that potentiates NF-kappaB signaling. |journal=Mol. Cell. Biol. |volume=23 |issue= 21 |pages= 7780–93 |year= 2003 |pmid= 14560022 |doi=10.1128/MCB.23.21.7780-7793.2003 | pmc=207563 }}
*{{Cite journal |vauthors=Ota T, Suzuki Y, Nishikawa T, etal |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40–5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
* {{cite journal | vauthors = tenOever BR, Sharma S, Zou W, Sun Q, Grandvaux N, Julkunen I, Hemmi H, Yamamoto M, Akira S, Yeh WC, Lin R, Hiscott J | display-authors = 6 | title = 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 = Journal of Virology | volume = 78 | issue = 19 | pages = 10636–10649 | date = October 2004 | pmid = 15367631 | pmc = 516426 | doi = 10.1128/JVI.78.19.10636-10649.2004 }}
*{{Cite journal |vauthors=Bouwmeester T, Bauch A, Ruffner H, etal |title=A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. |journal=Nat. Cell Biol. |volume=6 |issue= 2 |pages= 97–105 |year= 2004 |pmid= 14743216 |doi= 10.1038/ncb1086 }}
* {{cite journal | vauthors = Kuai J, Wooters J, Hall JP, Rao VR, Nickbarg E, Li B, Chatterjee-Kishore M, Qiu Y, Lin LL | display-authors = 6 | title = 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 | journal = The Journal of Biological Chemistry | volume = 279 | issue = 51 | pages = 53266–53271 | date = December 2004 | pmid = 15485837 | doi = 10.1074/jbc.M411037200 | doi-access = free }}
⚫
* {{cite journal | vauthors = Buss H, Dörrie A, Schmitz ML, Hoffmann E, Resch K, Kracht M | title = 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 | journal = The Journal of Biological Chemistry | volume = 279 | issue = 53 | pages = 55633–55643 | date = December 2004 | pmid = 15489227 | doi = 10.1074/jbc.M409825200 | doi-access = free }}
*{{Cite journal |vauthors=tenOever BR, Sharma S, Zou W, etal |title=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=J. Virol. |volume=78 |issue= 19 |pages= 10636–49 |year= 2004 |pmid= 15367631 |doi= 10.1128/JVI.78.19.10636-10649.2004 | pmc=516426 }}
*{{Cite journal |vauthors=Kuai J, Wooters J, Hall JP, etal |title=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. |journal=J. Biol. Chem. |volume=279 |issue= 51 |pages= 53266–71 |year= 2005 |pmid= 15485837 |doi= 10.1074/jbc.M411037200 }}
⚫
*{{Cite journal |vauthors=Buss H, Dörrie A, Schmitz ML, etal |title=Constitutive and interleukin-1-inducible phosphorylation of p65 NF-<nowiki/>{kappa}B at serine 536 is mediated by multiple protein kinases including I{kappa}B kinase (IKK)-<nowiki/>{alpha}, IKK{beta}, IKK{epsilon}, 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. |journal=J. Biol. Chem. |volume=279 |issue= 53 |pages= 55633–43 |year= 2005 |pmid= 15489227 |doi= 10.1074/jbc.M409825200 }}
{{Refend}}
{{Refend}}


{{Serine/threonine-specific protein kinases}}
{{Serine/threonine-specific protein kinases}}
{{Enzymes}}
{{Enzymes}}
{{Portal bar|Molecular and Cellular Biology|border=no}}
{{Portal bar|Biology|border=no}}



[[Category:EC 2.7.11]]
[[Category:EC 2.7.11]]

Latest revision as of 02:20, 10 October 2024

TBK1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTBK1, Tbk1, 1200008B05Rik, AI462036, AW048562, NAK, T2K, FTDALS4, TANK binding kinase 1, IIAE8
External IDsOMIM: 604834; MGI: 1929658; HomoloGene: 22742; GeneCards: TBK1; OMA:TBK1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

29110

56480

Ensembl

ENSG00000183735

ENSMUSG00000020115

UniProt

Q9UHD2

Q9WUN2

RefSeq (mRNA)

NM_013254

NM_019786

RefSeq (protein)

NP_037386

NP_062760

Location (UCSC)Chr 12: 64.45 – 64.5 MbChr 10: 121.38 – 121.42 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

TBK1 (TANK-binding kinase 1) is an enzyme with kinase activity. Specifically, it is a serine / threonine protein kinase.[5] It is encoded by the TBK1 gene in humans.[6] 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.[5] Insufficient regulation of TBK1 activity leads to autoimmune, neurodegenerative diseases or tumorigenesis.[7][8]

Structure and regulation of activity

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TBK1 is a non-canonical IKK kinase that phosphorylates the nuclear factor kB (NFkB). It shares sequence homology with canonical IKK.[5]

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.[5][6]

The autophosphorylation of serine 172, which requires homodimerization and ubiquitinylation of lysines 30 and 401, is necessary for kinase activity.[9]

Involvement in signaling pathways

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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.[5]

A key interest in TBK1 is due to its role in innate immunity, especially in antiviral responses. TBK1 is redundant with IKK, 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.[7]

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.[10]

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.[6]

TBK1 promotes autophagy involved in pathogen and mitochondrial clearance.[11] TBK1 phosphorylates autophagy receptors [12][13] and components of the autophagy apparatus.[14][15] Furthermore, TBK1 is also involved in the regulation of cell proliferation, apoptosis and glucose metabolism.[10]

Interactions

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

Transcription factors activated upon TBK1 activation include IRF3, IRF7[21] and ZEB1. [22]

Clinical significance

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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.[8] There are also many autoimmune (e.g., rheumatoid arthritis, sympathetic lupus), neurodegenerative (e.g., amyotrophic lateral sclerosis), and infantile (e.g., herpesviral encephalitis) diseases.[9][7]

The loss of TBK1 cause embryonic lethality in mice.[21]

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,[23] and a way to overcome resistance to cancer immunotherapy.[24]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000183735 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020115 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c d e Helgason E, Phung QT, Dueber EC (April 2013). "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. doi:10.1016/j.febslet.2013.01.059. PMID 23395801.
  6. ^ a b c "Entrez Gene: TBK1 TANK-binding kinase 1".
  7. ^ a b c Louis C, Burns C, Wicks I (2018-03-06). "TANK-Binding Kinase 1-Dependent Responses in Health and Autoimmunity". Frontiers in Immunology. 9: 434. doi:10.3389/fimmu.2018.00434. PMC 5845716. PMID 29559975.
  8. ^ a b Cruz VH, Brekken RA (March 2018). "Assessment of TANK-binding kinase 1 as a therapeutic target in cancer". Journal of Cell Communication and Signaling. 12 (1): 83–90. doi:10.1007/s12079-017-0438-y. PMC 5842199. PMID 29218456.
  9. ^ a b Oakes JA, Davies MC, Collins MO (February 2017). "TBK1: a new player in ALS linking autophagy and neuroinflammation". Molecular Brain. 10 (1): 5. doi:10.1186/s13041-017-0287-x. PMC 5288885. PMID 28148298.
  10. ^ a b Durand JK, Zhang Q, Baldwin AS (September 2018). "Roles for the IKK-Related Kinases TBK1 and IKKε in Cancer". Cells. 7 (9): 139. doi:10.3390/cells7090139. PMC 6162516. PMID 30223576.
  11. ^ von Muhlinen N, Thurston T, Ryzhakov G, Bloor S, Randow F (February 2010). "NDP52, a novel autophagy receptor for ubiquitin-decorated cytosolic bacteria". Autophagy. 6 (2): 288–289. doi:10.4161/auto.6.2.11118. PMID 20104023. S2CID 1059428.
  12. ^ Pilli M, Arko-Mensah J, Ponpuak M, Roberts E, Master S, Mandell MA, et al. (August 2012). "TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation". Immunity. 37 (2): 223–234. doi:10.1016/j.immuni.2012.04.015. PMC 3428731. PMID 22921120.
  13. ^ Richter B, Sliter DA, Herhaus L, Stolz A, Wang C, Beli P, et al. (April 2016). "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. Bibcode:2016PNAS..113.4039R. doi:10.1073/pnas.1523926113. PMC 4839414. PMID 27035970.
  14. ^ Kumar S, Gu Y, Abudu YP, Bruun JA, Jain A, Farzam F, et al. (April 2019). "Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation". Developmental Cell. 49 (1): 130–144.e6. doi:10.1016/j.devcel.2019.01.027. PMC 6907693. PMID 30827897.
  15. ^ Herhaus L, Bhaskara RM, Lystad AH, Gestal-Mato U, Covarrubias-Pinto A, Bonn F, et al. (January 2020). "TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls autophagosome shedding by ATG4 protease". EMBO Reports. 21 (1): e48317. doi:10.15252/embr.201948317. PMC 6945063. PMID 31709703.
  16. ^ Chou MM, Hanafusa H (March 1995). "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. doi:10.1074/jbc.270.13.7359. PMID 7706279.
  17. ^ Pomerantz JL, Baltimore D (December 1999). "NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase". The EMBO Journal. 18 (23): 6694–6704. doi:10.1093/emboj/18.23.6694. PMC 1171732. PMID 10581243.
  18. ^ a b Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, et al. (February 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology. 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216. S2CID 11683986.
  19. ^ Bonnard M, Mirtsos C, Suzuki S, Graham K, Huang J, Ng M, et al. (September 2000). "Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription". The EMBO Journal. 19 (18): 4976–4985. doi:10.1093/emboj/19.18.4976. PMC 314216. PMID 10990461.
  20. ^ "TANK-binding kinase 1-binding protein 1". UniProt. Retrieved 30 Jun 2018.
  21. ^ a b Ikeda F, Hecker CM, Rozenknop A, Nordmeier RD, Rogov V, Hofmann K, et al. (July 2007). "Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes". The EMBO Journal. 26 (14): 3451–3462. doi:10.1038/sj.emboj.7601773. PMC 1933404. PMID 17599067.
  22. ^ Liu W, Huang YJ, Liu C, Yang YY, Liu H, Cui JG, et al. (April 2014). "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. doi:10.1038/labinvest.2013.153. PMID 24468793.
  23. ^ Llona-Minguez S, Baiget J, Mackay SP (July 2013). "Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases". Pharmaceutical Patent Analyst. 2 (4): 481–498. doi:10.4155/ppa.13.31. PMID 24237125.
  24. ^ Sun, Y.; Anderson, S. (January 12, 2023). "Targeting TBK1 to overcome resistance to cancer immunotherapy". Nature. 615 (7950): 158–167. Bibcode:2023Natur.615..158S. doi:10.1038/s41586-023-05704-6. PMC 10171827. PMID 36634707.

Further reading

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