Biology:TANK-binding kinase 1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1] 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.[1]

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.[1][2]

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.[1]

A key interest in TBK1 is due to its role in innate immunity, especially in antiviral responses. TBK1 is redundant with IKK[math]\displaystyle{ \epsilon }[/math], 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.[3]

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.[2]

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.[6]

Interactions

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


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.[4] There are also many autoimmune (e.g., rheumatoid arthritis, sympathetic lupus), neurodegenerative (e.g., amyotrophic lateral sclerosis), and infantile (e.g., herpesviral encephalitis) diseases.[5][3]

The loss of TBK1 cause embryonic lethality in mice.[17]

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

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "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. doi:10.1016/j.febslet.2013.01.059. PMID 23395801. 
  2. ↑ 2.0 2.1 2.2 "Entrez Gene: TBK1 TANK-binding kinase 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=29110. 
  3. ↑ 3.0 3.1 3.2 "TANK-Binding Kinase 1-Dependent Responses in Health and Autoimmunity". Frontiers in Immunology 9: 434. 2018-03-06. doi:10.3389/fimmu.2018.00434. PMID 29559975. 
  4. ↑ 4.0 4.1 "Assessment of TANK-binding kinase 1 as a therapeutic target in cancer". Journal of Cell Communication and Signaling 12 (1): 83–90. March 2018. doi:10.1007/s12079-017-0438-y. PMID 29218456. 
  5. ↑ 5.0 5.1 "TBK1: a new player in ALS linking autophagy and neuroinflammation". Molecular Brain 10 (1): 5. February 2017. doi:10.1186/s13041-017-0287-x. PMID 28148298. 
  6. ↑ 6.0 6.1 "Roles for the IKK-Related Kinases TBK1 and IKKε in Cancer". Cells 7 (9): 139. September 2018. doi:10.3390/cells7090139. PMID 30223576. 
  7. ↑ "NDP52, a novel autophagy receptor for ubiquitin-decorated cytosolic bacteria". Autophagy 6 (2): 288–289. February 2010. doi:10.4161/auto.6.2.11118. PMID 20104023. 
  8. ↑ "TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation". Immunity 37 (2): 223–234. August 2012. doi:10.1016/j.immuni.2012.04.015. PMID 22921120. 
  9. ↑ "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. doi:10.1073/pnas.1523926113. PMID 27035970. Bibcode: 2016PNAS..113.4039R. 
  10. ↑ "Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation". Developmental Cell 49 (1): 130–144.e6. April 2019. doi:10.1016/j.devcel.2019.01.027. PMID 30827897. 
  11. ↑ "TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls autophagosome shedding by ATG4 protease". EMBO Reports 21 (1): e48317. January 2020. doi:10.15252/embr.201948317. PMID 31709703. 
  12. ↑ "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. doi:10.1074/jbc.270.13.7359. PMID 7706279. 
  13. ↑ "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. doi:10.1093/emboj/18.23.6694. PMID 10581243. 
  14. ↑ 14.0 14.1 "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. doi:10.1038/ncb1086. PMID 14743216. 
  15. ↑ "Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription". The EMBO Journal 19 (18): 4976–4985. September 2000. doi:10.1093/emboj/19.18.4976. PMID 10990461. 
  16. ↑ "TANK-binding kinase 1-binding protein 1". https://www.uniprot.org/uniprot/A7MCY6. 
  17. ↑ 17.0 17.1 "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. doi:10.1038/sj.emboj.7601773. PMID 17599067. 
  18. ↑ "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. doi:10.1038/labinvest.2013.153. PMID 24468793. 
  19. ↑ "Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases". Pharmaceutical Patent Analyst 2 (4): 481–498. July 2013. doi:10.4155/ppa.13.31. PMID 24237125. 
  20. ↑ Sun, Y.; Anderson, S. (January 12, 2023). "Targeting TBK1 to overcome resistance to cancer immunotherapy". Nature 615 (7950): 158–167. doi:10.1038/s41586-023-05704-6. PMID 36634707. Bibcode: 2023Natur.615..158S. 

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