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 tumorogenesis.[7][8]

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
Gene location (Human)
Chromosome 12 (human)
Chr.Chromosome 12 (human)[1]
Chromosome 12 (human)
Genomic location for TBK1
Genomic location for TBK1
Band12q14.2Start64,452,092 bp[1]
End64,502,114 bp[1]
RNA expression pattern
PBB GE TBK1 218520 at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_013254

NM_019786

RefSeq (protein)

NP_037386

NP_062760

Location (UCSC)Chr 12: 64.45 – 64.5 MbChr 10: 121.55 – 121.59 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure and regulation of activityEdit

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 pathwaysEdit

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 (INF-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 [disambiguation needed], 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 INF-I.[7]

As a non-canonical IKK, TBK1 is also involved in the non-canonical NFkB pathway. It phosphorylates p100/NFkB2, 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 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.[6]

TBK1 promotes autophagy involved in pathogen clearance. Furthermore, TBK1 is also involved in the regulation of cell proliferation, apoptosis and glucose metabolism.[10]

InteractionsEdit

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

Transcription factors activated upon TBK1 activation include IRF3, IRF7 [16] and ZEB1. [17]

Clinical significanceEdit

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.[16]

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.[18]

See alsoEdit

ReferencesEdit

  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): 1230–7. 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. ^ 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): 7359–64. doi:10.1074/jbc.270.13.7359. PMID 7706279.
  12. ^ 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): 6694–704. doi:10.1093/emboj/18.23.6694. PMC 1171732. PMID 10581243.
  13. ^ 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.
  14. ^ 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): 4976–85. doi:10.1093/emboj/19.18.4976. PMC 314216. PMID 10990461.
  15. ^ "TANK-binding kinase 1-binding protein 1". UniProt. Retrieved 30 Jun 2018.
  16. ^ 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): 3451–62. doi:10.1038/sj.emboj.7601773. PMC 1933404. PMID 17599067.
  17. ^ 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): 362–70. doi:10.1038/labinvest.2013.153. PMID 24468793.
  18. ^ 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): 481–98. doi:10.4155/ppa.13.31. PMID 24237125.

Further readingEdit