TBK1 (TANK binding kinase 1)

Gene

• Entrez ID: 29110
• Gene name: TANK binding kinase 1
• Gene symbol: TBK1
• Synonyms: FTDALS4, IIAE8, NAK, T2K
• Chromosome: 12
• Chromosome location: 12q14.2
• Summary: 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. [provided by RefSeq, Oct 2010]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs55824172	C>G,T	Likely-pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs142030898	C>T	Other, pathogenic	Non coding transcript variant, stop gained, coding sequence variant
rs748112833	G>A	Pathogenic	Coding sequence variant, missense variant, non coding transcript variant
rs755950225	A>-	Pathogenic	Non coding transcript variant, frameshift variant, coding sequence variant
rs756751089	A>G	Pathogenic	Missense variant, non coding transcript variant, coding sequence variant
rs767898276	G>A	Pathogenic	Splice donor variant
rs876657404	TTAA>-	Pathogenic	Non coding transcript variant, coding sequence variant, frameshift variant
rs876657405	TG>-	Pathogenic	Non coding transcript variant, coding sequence variant, frameshift variant
rs876657406	T>C	Pathogenic	Splice donor variant
rs905184241	C>G	Uncertain-significance, likely-pathogenic	Non coding transcript variant, coding sequence variant, missense variant
rs1010930015	A>C	Risk-factor	Missense variant, non coding transcript variant, coding sequence variant
rs1027249002	C>A,T	Pathogenic	Non coding transcript variant, missense variant, coding sequence variant
rs1064797170	C>T	Likely-pathogenic	Non coding transcript variant, stop gained, coding sequence variant
rs1328949478	C>T	Pathogenic	Stop gained, non coding transcript variant, coding sequence variant
rs1341055534	G>A	Pathogenic	Splice donor variant
rs1402092579	AAG>-	Pathogenic	Inframe deletion, coding sequence variant, non coding transcript variant
rs1555202947	G>C	Risk-factor	Missense variant, non coding transcript variant, coding sequence variant
rs1555203557	A>G	Risk-factor	Missense variant, non coding transcript variant, coding sequence variant
rs1555204731	GA>-	Pathogenic	Frameshift variant, non coding transcript variant, coding sequence variant
rs1565814492	->A	Pathogenic	Frameshift variant, coding sequence variant, non coding transcript variant
rs1565825132	G>T	Likely-pathogenic	Stop gained, coding sequence variant, non coding transcript variant
rs1592350883	->A	Pathogenic	Frameshift variant, coding sequence variant, non coding transcript variant
rs1592350887	G>A	Pathogenic	Synonymous variant, coding sequence variant, non coding transcript variant
rs1592362719	G>A	Likely-pathogenic	Splice donor variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT003360	hsa-miR-221-3p	Reporter assay;Western blot;Microarray	20018759
MIRT006971	hsa-miR-200c-3p	Luciferase reporter assay, Western blot	22991189
MIRT006971	hsa-miR-200c-3p	PAR-CLIP	24398324
MIRT053453	hsa-miR-452-5p	Microarray	23807165
MIRT066413	hsa-let-7f-2-3p	PAR-CLIP	23446348
MIRT066413	hsa-let-7f-2-3p	PAR-CLIP	20371350
MIRT066414	hsa-miR-1185-2-3p	PAR-CLIP	23446348
MIRT066414	hsa-miR-1185-2-3p	PAR-CLIP	20371350
MIRT066415	hsa-miR-1185-1-3p	PAR-CLIP	23446348
MIRT066415	hsa-miR-1185-1-3p	PAR-CLIP	20371350
MIRT066418	hsa-miR-6792-5p	PAR-CLIP	23446348
MIRT066418	hsa-miR-6792-5p	PAR-CLIP	20371350
MIRT500831	hsa-miR-3671	PAR-CLIP	24398324
MIRT500832	hsa-miR-3674	PAR-CLIP	24398324
MIRT500833	hsa-miR-219b-3p	PAR-CLIP	24398324
MIRT500834	hsa-miR-4680-3p	PAR-CLIP	24398324
MIRT500835	hsa-miR-429	PAR-CLIP	24398324
MIRT500836	hsa-miR-4724-5p	PAR-CLIP	24398324
MIRT500837	hsa-miR-200b-3p	PAR-CLIP	24398324
MIRT500838	hsa-miR-219a-2-3p	PAR-CLIP	24398324
MIRT517391	hsa-miR-186-5p	PAR-CLIP	23446348
MIRT517391	hsa-miR-186-5p	PAR-CLIP	20371350
MIRT517392	hsa-miR-3133	PAR-CLIP	23446348
MIRT517392	hsa-miR-3133	PAR-CLIP	20371350
MIRT733529	hsa-miR-203a-3p	Luciferase reporter assay, qRT-PCR, Western blot	26584294

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0002218	Process	Activation of innate immune response	IEA
GO:0003676	Function	Nucleic acid binding	IEA
GO:0004672	Function	Protein kinase activity	TAS
GO:0004674	Function	Protein serine/threonine kinase activity	IBA	21873635
GO:0004674	Function	Protein serine/threonine kinase activity	IDA	25636800, 25803835, 27103069
GO:0004674	Function	Protein serine/threonine kinase activity	TAS	21042276
GO:0005515	Function	Protein binding	IPI	14743216, 15841462, 16281057, 16306936, 17568778, 17599067, 18307994, 18583960, 18636086, 18724357, 19153231, 19380580, 19416887, 19419966, 19433799, 20098747, 20174559, 20562859, 20628368, 21813773, 21903422, 21931555, 21988832, 22000020, 22939624, 23096996, 23414517, 23542348, 240
GO:0005524	Function	ATP binding	IEA
GO:0005654	Component	Nucleoplasm	IDA
GO:0005737	Component	Cytoplasm	IBA	21873635
GO:0005737	Component	Cytoplasm	IDA	21813773, 29251827
GO:0005829	Component	Cytosol	TAS
GO:0006468	Process	Protein phosphorylation	IDA	27103069
GO:0006954	Process	Inflammatory response	TAS	21042276
GO:0007249	Process	I-kappaB kinase/NF-kappaB signaling	TAS	21042276
GO:0009615	Process	Response to virus	TAS	21042276
GO:0010008	Component	Endosome membrane	TAS
GO:0016032	Process	Viral process	IEA
GO:0016239	Process	Positive regulation of macroautophagy	IDA	27103069
GO:0018105	Process	Peptidyl-serine phosphorylation	IBA	21873635
GO:0018105	Process	Peptidyl-serine phosphorylation	IDA	25636800, 25803835, 27103069
GO:0018107	Process	Peptidyl-threonine phosphorylation	IDA	25636800, 27103069
GO:0019903	Function	Protein phosphatase binding	ISS
GO:0032479	Process	Regulation of type I interferon production	IDA	25636800
GO:0032479	Process	Regulation of type I interferon production	TAS
GO:0032480	Process	Negative regulation of type I interferon production	TAS
GO:0032481	Process	Positive regulation of type I interferon production	TAS
GO:0032606	Process	Type I interferon production	TAS	21042276
GO:0032727	Process	Positive regulation of interferon-alpha production	IDA	16127453
GO:0032728	Process	Positive regulation of interferon-beta production	IDA	16127453
GO:0033138	Process	Positive regulation of peptidyl-serine phosphorylation	NAS	22412986
GO:0035666	Process	TRIF-dependent toll-like receptor signaling pathway	TAS
GO:0042802	Function	Identical protein binding	IEA
GO:0043123	Process	Positive regulation of I-kappaB kinase/NF-kappaB signaling	IEP	12761501
GO:0043231	Component	Intracellular membrane-bounded organelle	IDA
GO:0044565	Process	Dendritic cell proliferation	IEA
GO:0045087	Process	Innate immune response	IDA	25636800
GO:0045087	Process	Innate immune response	TAS	21042276
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	IDA	16127453
GO:0050830	Process	Defense response to Gram-positive bacterium	IEA
GO:0051219	Function	Phosphoprotein binding	IPI	14530355
GO:0051607	Process	Defense response to virus	IEA
GO:0060340	Process	Positive regulation of type I interferon-mediated signaling pathway	IEA
GO:0071345	Process	Cellular response to cytokine stimulus	TAS
GO:0106310	Function	Protein serine kinase activity	IEA
GO:0106311	Function	Protein threonine kinase activity	IEA
GO:1901214	Process	Regulation of neuron death	NAS	25803835
GO:1904417	Process	Positive regulation of xenophagy	IEA

Other IDs

• MIM: 604834
• HGNC: 11584
• e!Ensembl: ENSG00000183735

Protein

• UniProt ID: Q9UHD2
• Protein name: Serine/threonine-protein kinase TBK1 (EC 2.7.11.1) (NF-kappa-B-activating kinase) (T2K) (TANK-binding kinase 1)
• Protein function: Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents (PubMed:12692549, PubMed:14703513, PubMed:18583960, PubMed:12702806, PubMed:15367631, PubMed:10581243, PubMed:11839743, PubMed:15485837, PubMed:21138416, PubMed:25636800, PubMed:23453971, PubMed:23453972, PubMed:23746807, PubMed:26611359, PubMed:32404352). Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X (PubMed:12692549, PubMed:14703513, PubMed:18583960, PubMed:12702806, PubMed:15367631, PubMed:25636800). This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB (PubMed:12702806, PubMed:15367631, PubMed:25636800, PubMed:32972995). In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli (PubMed:23453971, PubMed:23453972, PubMed:23746807). Plays a key role in IRF3 activation: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 (PubMed:25636800, PubMed:30842653). Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce expression of interferons (PubMed:25636800). Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes (PubMed:21931631). Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus (PubMed:10783893, PubMed:15489227). Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy (PubMed:21617041). Phosphorylates SMCR8 component of the C9orf72-SMCR8 complex, promoting autophagosome maturation (PubMed:27103069). Phosphorylates and activates AKT1 (PubMed:21464307). Seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity (By similarity). Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C (PubMed:21270402). Phosphorylates Borna disease virus (BDV) P protein (PubMed:16155125). Plays an essential role in the TLR3- and IFN-dependent control of herpes virus HSV-1 and HSV-2 infections in the central nervous system (PubMed:22851595).
• PDB: 4EFO, 4EUT, 4EUU, 4IM0, 4IM2, 4IM3, 4IW0, 4IWO, 4IWP, 4IWQ, 5EOA, 5EOF, 5EP6, 5W5V, 6BNY, 6BOD, 6BOE, 6CQ0, 6CQ4, 6CQ5, 6NT9, 6O8B, 6RSR, 6RST, 6RSU
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00069	Pkinase	9 → 299	Protein kinase domain	Domain
  PF18396	TBK1_ULD	308 → 395	TANK binding kinase 1 ubiquitin-like domain	Domain
  PF18394	TBK1_CCD1	400 → 655	TANK-binding kinase 1 coiled-coil domain 1	Coiled-coil

• Sequence:

  MQSTSNHLWLLSDILGQGATANVFRGRHKKTGDLFAIKVFNNISFLRPVDVQMREFEVLK
  KLNHKNIVKLFAIEEETTTRHKVLIMEFCPCGSLYTVLEEPSNAYGLPESEFLIVLRDVV
  GGMNHLRENGIVHRDIKPGNIMRVIGEDGQSVYKLTDFGAARELEDDEQFVSLYGTEEYL
  HPDMYERAVLRKDHQKKYGATVDLWSIGVTFYHAATGSLPFRPFEGPRRNKEVMYKIITG
  KPSGAISGVQKAENGPIDWSGDMPVSCSLSRGLQVLLTPVLANILEADQEKCWGFDQFFA
  ETSDILHRMVIHVFSLQQMTAHKIYIHSYNTATIFHELVYKQTKIISSNQELIYEGRRLV
  LEPGRLAQHFPKTTEENPIFVVSREPLNTIGLIYEKISLPKVHPRYDLDGDASMAKAITG
  VVCYACRIASTLLLYQELMRKGIRWLIELIKDDYNETVHKKTEVVITLDFCIRNIEKTVK
  VYEKLMKINLEAAELGEISDIHTKLLRLSSSQGTIETSLQDIDSRLSPGGSLADAWAHQE
  GTHPKDRNVEKLQVLLNCMTEIYYQFKKDKAERRLAYNEEQIHKFDKQKLYYHATKAMTH
  FTDECVKKYEAFLNKSEEWIRKMLHLRKQLLSLTNQCFDIEEEVSKYQEYTNELQETLPQ
  KMFTASSGIKHTMTPIYPSSNTLVEMTLGMKKLKEEMEGVVKELAENNHILERFGSLTMD
  GGLRNVDCL

• Sequence length: 729