ID:TBK1_HUMAN DESCRIPTION: RecName: Full=Serine/threonine-protein kinase TBK1; EC=2.7.11.1; AltName: Full=NF-kappa-B-activating kinase; AltName: Full=T2K; AltName: Full=TANK-binding kinase 1; FUNCTION: Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. 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. This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFN- alpha and IFN-beta. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including FADD, TRADD, MAVS or SINTBAD can be recruited to the TBK1-containing-complexes. 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. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy. Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C. Phosphorylates and activates AKT1. Phosphorylates Borna disease virus (BDV) P protein. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. SUBUNIT: Self-associates. Interacts with TIRAP, TANK and TRAF2. Part of a ternary complex consisting of TANK, TRAF2 and TBK1. Interacts with AZI2; this interaction mediates TBK1 activation. Interacts with GSK3B; this interaction promotes TBK1 self- association and autophosphorylation. Interacts with SIKE1; SIKE1 is associated with TBK1 under physiological condition and dissociated from TBK1 upon viral infection or TLR3 stimulation. Interacts with TICAM1/TRIF, IRF3 and DDX58/RIG-I. Interacts with CYLD. Interacts with HCV NS3, Ebola virus VP35 and Borna disease virus protein P; these interactions lead to inhibition of cellular antiviral response by blocking necessary interactions between the TBK1 and its substrates IRF3 and IRF7. Interacts with OPTN and TRAF3. Interacts with SRC. Interacts with the exocyst complex subunit SEC5/EXOC2; this interaction is sufficient to trigger TBK1 activity. Interacts with TMEM173/MITA. Interacts with IFIT3 (via N-terminus). Interacts with MAVS only in the presence of IFIT3. INTERACTION: P27958:- (xeno); NbExp=4; IntAct=EBI-356402, EBI-3649474; Q7Z3C6:ATG9A; NbExp=2; IntAct=EBI-356402, EBI-727146; Q13137:CALCOCO2; NbExp=5; IntAct=EBI-356402, EBI-739580; Q6DT37:CDC42BPG; NbExp=2; IntAct=EBI-356402, EBI-689124; Q9BZA4:CYorf15B; NbExp=2; IntAct=EBI-356402, EBI-6115828; Q9UKV8:EIF2C2; NbExp=2; IntAct=EBI-356402, EBI-528269; Q14653:IRF3; NbExp=4; IntAct=EBI-356402, EBI-2650369; Q86YT6:MIB1; NbExp=2; IntAct=EBI-356402, EBI-2129148; Q96AX9:MIB2; NbExp=2; IntAct=EBI-356402, EBI-2130249; Q9NVV4:MTPAP; NbExp=2; IntAct=EBI-356402, EBI-2556166; Q96CV9:OPTN; NbExp=3; IntAct=EBI-356402, EBI-748974; P42226:STAT6; NbExp=7; IntAct=EBI-356402, EBI-1186478; Q92844:TANK; NbExp=3; IntAct=EBI-356402, EBI-356349; P40222:TXLNA; NbExp=4; IntAct=EBI-356402, EBI-359793; Q8BHN1:Txlng (xeno); NbExp=2; IntAct=EBI-356402, EBI-6116854; SUBCELLULAR LOCATION: Cytoplasm. Note=Upon mitogen stimulation or triggering of the immune system, TBK1 is recruited to the exocyst by EXOC2. TISSUE SPECIFICITY: Ubiquitous with higher expression in testis. DOMAIN: Comprises A N-terminal kinase domain, an ubiquitin-like domain and a C-terminal leucine-zipper. PTM: Autophosphorylation at Ser-172 activates the kinase, and is an essential step for virus-triggered signaling. Phosphorylated by IKBKB/IKKB at Ser-172. PTM: 'Lys-63'-linked polyubiquitination by MIB1 after RNA virus infection, or by NRDP1 after LPS stimulation, may participate in kinase activation. 'Lys-48'-linked polyubiquitination at Lys-670 by DTX4 leads to proteasomal degradation. MISCELLANEOUS: In cancer cells, pathological TBK1 activation promotes oncogenic transformation by suppressing programmed cell death. Mechanistically, the RALB-SEC5/EXOC2-TBK1 signaling cascade seems to participate in both innate immune signaling and cell transformation. Additionally, TBK1 supports oncogenesis by directly phosphorylating and activating AKT1 at the exocyst (PubMed:21042276). SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. SIMILARITY: Contains 1 protein kinase domain. SIMILARITY: Contains 1 ubiquitin-like domain. SEQUENCE CAUTION: Sequence=BAA92129.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q9UHD2
Front
Top
Side
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.
Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0002218 activation of innate immune response GO:0002376 immune system process GO:0006468 protein phosphorylation GO:0006954 inflammatory response GO:0007249 I-kappaB kinase/NF-kappaB signaling GO:0009615 response to virus GO:0010629 negative regulation of gene expression GO:0016032 viral process GO:0016239 positive regulation of macroautophagy GO:0016310 phosphorylation GO:0018105 peptidyl-serine phosphorylation GO:0018107 peptidyl-threonine phosphorylation GO:0032479 regulation of type I interferon production GO:0032480 negative regulation of type I interferon production GO:0032481 positive regulation of type I interferon production GO:0032606 type I interferon production GO:0032727 positive regulation of interferon-alpha production GO:0032728 positive regulation of interferon-beta production GO:0033138 positive regulation of peptidyl-serine phosphorylation GO:0035666 TRIF-dependent toll-like receptor signaling pathway GO:0043123 positive regulation of I-kappaB kinase/NF-kappaB signaling GO:0044565 dendritic cell proliferation GO:0045087 innate immune response GO:0045359 positive regulation of interferon-beta biosynthetic process GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0050830 defense response to Gram-positive bacterium GO:0051607 defense response to virus GO:0071345 cellular response to cytokine stimulus GO:1901214 regulation of neuron death GO:1904417 positive regulation of xenophagy
AK291039 - Homo sapiens cDNA FLJ75314 complete cds, highly similar to Homo sapiens TANK binding kinase TBK1 (TBK1) mRNA. BC034950 - Homo sapiens TANK-binding kinase 1, mRNA (cDNA clone MGC:26196 IMAGE:4824988), complete cds. LP895250 - Sequence 114 from Patent EP3253886. AF191838 - Homo sapiens TANK binding kinase TBK1 (TBK1) mRNA, complete cds. AB591015 - Synthetic construct DNA, clone: pFN21AB5724, Homo sapiens TBK1 gene for TANK-binding kinase 1, without stop codon, in Flexi system. KJ898722 - Synthetic construct Homo sapiens clone ccsbBroadEn_08116 TBK1 gene, encodes complete protein. KJ905460 - Synthetic construct Homo sapiens clone ccsbBroadEn_15050 TBK1 gene, encodes complete protein. AF174536 - Homo sapiens NF-kB-activating kinase NAK mRNA, complete cds. AK303683 - Homo sapiens cDNA FLJ56613 complete cds, highly similar to Serine/threonine-protein kinase TBK1 (EC 2.7.11.1). AK002192 - Homo sapiens cDNA FLJ11330 fis, clone PLACE1010529. CU689990 - Synthetic construct Homo sapiens gateway clone IMAGE:100020408 5' read TBK1 mRNA. MS839218 - Sequence 331 from Patent WO2017013436. MA790380 - JP 2018524990-A/331: Molecular Diagnostic Test for Cancer. JD166518 - Sequence 147542 from Patent EP1572962. JD155153 - Sequence 136177 from Patent EP1572962.
Biochemical and Signaling Pathways
Reactome (by CSHL, EBI, and GO)
Protein Q9UHD2 (Reactome details) participates in the following event(s):
R-HSA-1606324 Recruitment TBK1 to dsDNA:ZBP1 followed by its activation R-HSA-1834939 STING recruits TBK1 and IRF3 R-HSA-3249378 STING recruits TBK1 and STAT6 R-HSA-2396002 TBK1 is phosphorylated within STING:TBK1:IRF3 complex R-HSA-3249390 TBK1 is phosphorylated within STING:TBK1:STAT6 complex R-HSA-936941 Recruitment of TBK1/IKK epsilon to K63-pUb-TANK:K63-pUb-TRAF3:TRIF:activated TLR4 followed by their phosphorylation R-HSA-937337 TAX1BP1:A20 inhibit TBK1/IKKi K63-polyubiquitination R-HSA-9013986 Recruitment of TBK1/IKK epsilon to K63-pUb-TANK:K63-pUb-TRAF3:TRIF:activated TLR3 followed by their phosphorylation R-HSA-1606345 Recruitment of IRF3 to activated ZBP1:TBK1 R-HSA-8948703 NLRP4 and DTX4 associate with p-S172-TBK1 within dsDNA:ZBP1:TBK1 R-HSA-1606327 Phosphorylation and release of IRF3 R-HSA-2396007 IRF3 is phosphorylated by TBK1 R-HSA-3249392 NLRP4 and DTX4 associate with p-S172-TBK1 within STING:TBK1:IRF3 R-HSA-3249371 TBK1 phosphorylates STAT6 at Ser407 R-HSA-3249386 DTX4 ubiquitinates p-S172-TBK1 within NLRP4:DTX4:dsDNA:ZBP1:TBK1 R-HSA-8948709 DTX4 ubiquitinates p-S172-TBK1 within NLRP4:DTX4:STING:TBK1:IRF3 R-HSA-918232 Recruitment of IRF3,IRF7 R-HSA-918225 TBK1/IKK epsilon complex interacts with MAVS bound TRAF3 R-HSA-918229 Phosphorylation and release of IRF3/IRF7 R-HSA-933527 Recruitment of TBK1/IKK epsilon complex to TANK:TRAF6 R-HSA-933538 Recruitment of IRF7 to TRAF6 R-HSA-933525 Phosphorylation and release of IRF7 R-HSA-166271 IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR4 R-HSA-166245 Phosphorylation of IRF-3/IRF7 and their release from the activated TLR complex R-HSA-9013979 IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR3 R-HSA-9013978 Phosphorylation of IRF-3/IRF7 and their release from the activated TLR3 complex R-HSA-1606341 IRF3 mediated activation of type 1 IFN R-HSA-3270619 IRF3-mediated induction of type I IFN R-HSA-3249367 STAT6-mediated induction of chemokines R-HSA-9008059 Interleukin-37 signaling R-HSA-936964 Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon R-HSA-936440 Negative regulators of DDX58/IFIH1 signaling R-HSA-9013973 TICAM1-dependent activation of IRF3/IRF7 R-HSA-1606322 ZBP1(DAI) mediated induction of type I IFNs R-HSA-1834941 STING mediated induction of host immune responses R-HSA-446652 Interleukin-1 family signaling R-HSA-3134975 Regulation of innate immune responses to cytosolic DNA R-HSA-918233 TRAF3-dependent IRF activation pathway R-HSA-933541 TRAF6 mediated IRF7 activation R-HSA-937061 TRIF(TICAM1)-mediated TLR4 signaling R-HSA-168928 DDX58/IFIH1-mediated induction of interferon-alpha/beta R-HSA-168164 Toll Like Receptor 3 (TLR3) Cascade R-HSA-1834949 Cytosolic sensors of pathogen-associated DNA R-HSA-449147 Signaling by Interleukins R-HSA-166166 MyD88-independent TLR4 cascade R-HSA-168249 Innate Immune System R-HSA-168898 Toll-Like Receptors Cascades R-HSA-1280215 Cytokine Signaling in Immune system R-HSA-166016 Toll Like Receptor 4 (TLR4) Cascade R-HSA-168256 Immune System
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
