TBK1_HUMAN
ID TBK1_HUMAN Reviewed; 729 AA.
AC Q9UHD2; A8K4S4; Q8IYV3; Q9NUJ5;
DT 20-DEC-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 198.
DE RecName: Full=Serine/threonine-protein kinase TBK1 {ECO:0000305};
DE EC=2.7.11.1 {ECO:0000269|PubMed:15367631, ECO:0000269|PubMed:18583960, ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:21270402, ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:21617041, ECO:0000269|PubMed:25636800};
DE AltName: Full=NF-kappa-B-activating kinase {ECO:0000303|PubMed:10783893};
DE AltName: Full=T2K;
DE AltName: Full=TANK-binding kinase 1 {ECO:0000303|PubMed:10581243};
GN Name=TBK1 {ECO:0000303|PubMed:10581243, ECO:0000312|HGNC:HGNC:11584};
GN Synonyms=NAK {ECO:0000303|PubMed:10783893};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH TANK AND TRAF2, AND
RP MUTAGENESIS OF LYS-38.
RC TISSUE=Spleen;
RX PubMed=10581243; DOI=10.1093/emboj/18.23.6694;
RA Pomerantz J.L., Baltimore D.;
RT "NF-kB activation by a signaling complex containing TRAF2, TANK, and TBK1,
RT a novel IKK-related kinase.";
RL EMBO J. 18:6694-6704(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION IN PHOSPHORYLATION OF NFKBIA AND
RP IKBKB, TISSUE SPECIFICITY, AND CATALYTIC ACTIVITY.
RX PubMed=10783893; DOI=10.1038/35008109;
RA Tojima Y., Fujimoto A., Delhase M., Chen Y., Hatakeyama S., Nakayama K.,
RA Kaneko Y., Nimura Y., Motoyama N., Ikeda K., Karin M., Nakanishi M.;
RT "NAK is an IkappaB kinase-activating kinase.";
RL Nature 404:778-782(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS ASP-388 AND GLN-570.
RC TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP FUNCTION, MUTAGENESIS OF SER-172, AND PHOSPHORYLATION AT SER-172.
RX PubMed=11839743; DOI=10.1074/jbc.m110474200;
RA Kishore N., Huynh Q.K., Mathialagan S., Hall T., Rouw S., Creely D.,
RA Lange G., Caroll J., Reitz B., Donnelly A., Boddupalli H., Combs R.G.,
RA Kretzmer K., Tripp C.S.;
RT "IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme IKK-
RT 2: comparative analysis of recombinant human IKK-i, TBK-1, and IKK-2.";
RL J. Biol. Chem. 277:13840-13847(2002).
RN [7]
RP INTERACTION WITH TIRAP AND TICAM1.
RX PubMed=14530355; DOI=10.4049/jimmunol.171.8.4304;
RA Sato S., Sugiyama M., Yamamoto M., Watanabe Y., Kawai T., Takeda K.,
RA Akira S.;
RT "Toll/IL-1 receptor domain-containing adapter inducing IFN-beta (TRIF)
RT associates with TNF receptor-associated factor 6 and TANK-binding kinase 1,
RT and activates two distinct transcription factors, NF-kappa B and IFN-
RT regulatory factor-3, in the Toll-like receptor signaling.";
RL J. Immunol. 171:4304-4310(2003).
RN [8]
RP FUNCTION.
RX PubMed=12692549; DOI=10.1038/ni921;
RA Fitzgerald K.A., McWhirter S.M., Faia K.L., Rowe D.C., Latz E.,
RA Golenbock D.T., Coyle A.J., Liao S.-M., Maniatis T.;
RT "IKKepsilon and TBK1 are essential components of the IRF3 signaling
RT pathway.";
RL Nat. Immunol. 4:491-496(2003).
RN [9]
RP FUNCTION.
RX PubMed=12702806; DOI=10.1126/science.1081315;
RA Sharma S., tenOever B.R., Grandvaux N., Zhou G.-P., Lin R., Hiscott J.;
RT "Triggering the interferon antiviral response through an IKK-related
RT pathway.";
RL Science 300:1148-1151(2003).
RN [10]
RP INTERACTION WITH AZI2.
RX PubMed=14560022; DOI=10.1128/mcb.23.21.7780-7793.2003;
RA Fujita F., Taniguchi Y., Kato T., Narita Y., Furuya A., Ogawa T.,
RA Sakurai H., Joh T., Itoh M., Delhase M., Karin M., Nakanishi M.;
RT "Identification of NAP1, a regulatory subunit of IkappaB kinase-related
RT kinases that potentiates NF-kappaB signaling.";
RL Mol. Cell. Biol. 23:7780-7793(2003).
RN [11]
RP FUNCTION IN PHOSPHORYLATION OF IRF3, AND CATALYTIC ACTIVITY.
RX PubMed=14703513; DOI=10.1074/jbc.m310616200;
RA Mori M., Yoneyama M., Ito T., Takahashi K., Inagaki F., Fujita T.;
RT "Identification of Ser-386 of interferon regulatory factor 3 as critical
RT target for inducible phosphorylation that determines activation.";
RL J. Biol. Chem. 279:9698-9702(2004).
RN [12]
RP INTERACTION WITH TICAM1.
RX PubMed=14739303; DOI=10.1074/jbc.m311629200;
RA Han K.J., Su X., Xu L.-G., Bin L.H., Zhang J., Shu H.-B.;
RT "Mechanisms of the TRIF-induced interferon-stimulated response element and
RT NF-kappaB activation and apoptosis pathways.";
RL J. Biol. Chem. 279:15652-15661(2004).
RN [13]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=15485837; DOI=10.1074/jbc.m411037200;
RA Kuai J., Wooters J., Hall J.P., Rao V.R., Nickbarg E., Li B.,
RA Chatterjee-Kishore M., Qiu Y., Lin L.-L.;
RT "NAK is recruited to the TNFR1 complex in a TNFalpha-dependent manner and
RT mediates the production of RANTES: identification of endogenous TNFR-
RT interacting proteins by a proteomic approach.";
RL J. Biol. Chem. 279:53266-53271(2004).
RN [14]
RP FUNCTION IN PHOSPHORYLATION OF RELA, AND CATALYTIC ACTIVITY.
RX PubMed=15489227; DOI=10.1074/jbc.m409825200;
RA Buss H., Dorrie A., Schmitz M.L., Hoffmann E., Resch K., Kracht M.;
RT "Constitutive and interleukin-1-inducible phosphorylation of p65
RT NF-{kappa}B at serine 536 is mediated by multiple protein kinases including
RT I{kappa}B kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF family
RT member-associated (TANK)-binding kinase 1 (TBK1), and an unknown kinase and
RT couples p65 to TATA-binding protein-associated factor II31-mediated
RT interleukin-8 transcription.";
RL J. Biol. Chem. 279:55633-55643(2004).
RN [15]
RP FUNCTION IN PHOSPHORYLATION OF IRF7, AND CATALYTIC ACTIVITY.
RX PubMed=15367631; DOI=10.1128/jvi.78.19.10636-10649.2004;
RA tenOever B.R., Sharma S., Zou W., Sun Q., Grandvaux N., Julkunen I.,
RA Hemmi H., Yamamoto M., Akira S., Yeh W.C., Lin R., Hiscott J.;
RT "Activation of TBK1 and IKKvarepsilon kinases by vesicular stomatitis virus
RT infection and the role of viral ribonucleoprotein in the development of
RT interferon antiviral immunity.";
RL J. Virol. 78:10636-10649(2004).
RN [16]
RP INTERACTION WITH SIKE1; IRF3; TICAM1 AND DDX58.
RX PubMed=16281057; DOI=10.1038/sj.emboj.7600863;
RA Huang J., Liu T., Xu L.-G., Chen D., Zhai Z., Shu H.-B.;
RT "SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-
RT triggered IRF-3 activation pathways.";
RL EMBO J. 24:4018-4028(2005).
RN [17]
RP INTERACTION WITH HCV NS3 (MICROBIAL INFECTION).
RX PubMed=15841462; DOI=10.1002/hep.20666;
RA Otsuka M., Kato N., Moriyama M., Taniguchi H., Wang Y., Dharel N.,
RA Kawabe T., Omata M.;
RT "Interaction between the HCV NS3 protein and the host TBK1 protein leads to
RT inhibition of cellular antiviral responses.";
RL Hepatology 41:1004-1012(2005).
RN [18]
RP FUNCTION, AND INTERACTION WITH BORNA DISEASE VIRUS P PROTEIN.
RX PubMed=16155125; DOI=10.1073/pnas.0502883102;
RA Unterstab G., Ludwig S., Anton A., Planz O., Dauber B., Krappmann D.,
RA Heins G., Ehrhardt C., Wolff T.;
RT "Viral targeting of the interferon-beta-inducing Traf family member-
RT associated NF-kappa-B activator (TANK)-binding kinase-1.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:13640-13645(2005).
RN [19]
RP INTERACTION WITH EXOC2, AND SUBCELLULAR LOCATION.
RX PubMed=17018283; DOI=10.1016/j.cell.2006.08.034;
RA Chien Y., Kim S., Bumeister R., Loo Y.M., Kwon S.W., Johnson C.L.,
RA Balakireva M.G., Romeo Y., Kopelovich L., Gale M. Jr., Yeaman C.,
RA Camonis J.H., Zhao Y., White M.A.;
RT "RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples
RT innate immune signaling to tumor cell survival.";
RL Cell 127:157-170(2006).
RN [20]
RP DOMAIN.
RX PubMed=17599067; DOI=10.1038/sj.emboj.7601773;
RA Ikeda F., Hecker C.M., Rozenknop A., Nordmeier R.D., Rogov V., Hofmann K.,
RA Akira S., Dotsch V., Dikic I.;
RT "Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in
RT regulation of IFN-inducible genes.";
RL EMBO J. 26:3451-3462(2007).
RN [21]
RP FUNCTION IN PHOSPHORYLATION OF DDX3X, AND CATALYTIC ACTIVITY.
RX PubMed=18583960; DOI=10.1038/emboj.2008.126;
RA Soulat D., Burckstummer T., Westermayer S., Goncalves A., Bauch A.,
RA Stefanovic A., Hantschel O., Bennett K.L., Decker T., Superti-Furga G.;
RT "The DEAD-box helicase DDX3X is a critical component of the TANK-binding
RT kinase 1-dependent innate immune response.";
RL EMBO J. 27:2135-2146(2008).
RN [22]
RP INTERACTION WITH CYLD.
RX PubMed=18636086; DOI=10.1038/embor.2008.136;
RA Friedman C.S., O'Donnell M.A., Legarda-Addison D., Ng A., Cardenas W.B.,
RA Yount J.S., Moran T.M., Basler C.F., Komuro A., Horvath C.M., Xavier R.,
RA Ting A.T.;
RT "The tumour suppressor CYLD is a negative regulator of RIG-I-mediated
RT antiviral response.";
RL EMBO Rep. 9:930-936(2008).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [24]
RP INTERACTION WITH SRC.
RX PubMed=19419966; DOI=10.1074/jbc.m808233200;
RA Johnsen I.B., Nguyen T.T., Bergstroem B., Fitzgerald K.A., Anthonsen M.W.;
RT "The tyrosine kinase c-Src enhances RIG-I (retinoic acid-inducible gene I)-
RT elicited antiviral signaling.";
RL J. Biol. Chem. 284:19122-19131(2009).
RN [25]
RP INTERACTION WITH EBOLAVIRUS PROTEIN VP35, AND AUTOPHOSPHORYLATION.
RX PubMed=19153231; DOI=10.1128/jvi.01875-08;
RA Prins K.C., Cardenas W.B., Basler C.F.;
RT "Ebola virus protein VP35 impairs the function of interferon regulatory
RT factor-activating kinases IKKepsilon and TBK-1.";
RL J. Virol. 83:3069-3077(2009).
RN [26]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [27]
RP UBIQUITINATION BY NRDP1.
RX PubMed=19483718; DOI=10.1038/ni.1742;
RA Wang C., Chen T., Zhang J., Yang M., Li N., Xu X., Cao X.;
RT "The E3 ubiquitin ligase Nrdp1 'preferentially' promotes TLR-mediated
RT production of type I interferon.";
RL Nat. Immunol. 10:744-752(2009).
RN [28]
RP INTERACTION WITH STING1.
RX PubMed=19416887; DOI=10.1073/pnas.0900818106;
RA Li Y., Li C., Xue P., Zhong B., Mao A.P., Ran Y., Chen H., Wang Y.Y.,
RA Yang F., Shu H.B.;
RT "ISG56 is a negative-feedback regulator of virus-triggered signaling and
RT cellular antiviral response.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:7945-7950(2009).
RN [29]
RP INTERACTION WITH HSP90AA1.
RX PubMed=20628368; DOI=10.1038/cr.2010.103;
RA Liu X.Y., Wei B., Shi H.X., Shan Y.F., Wang C.;
RT "Tom70 mediates activation of interferon regulatory factor 3 on
RT mitochondria.";
RL Cell Res. 20:994-1011(2010).
RN [30]
RP AUTOPHOSPHORYLATION, SUBUNIT, AND INTERACTION WITH GSK3B.
RX PubMed=21145761; DOI=10.1016/j.immuni.2010.11.021;
RA Lei C.Q., Zhong B., Zhang Y., Zhang J., Wang S., Shu H.B.;
RT "Glycogen synthase kinase 3beta regulates IRF3 transcription factor-
RT mediated antiviral response via activation of the kinase TBK1.";
RL Immunity 33:878-889(2010).
RN [31]
RP INTERACTION WITH DDX3X.
RX PubMed=20375222; DOI=10.1099/vir.0.020552-0;
RA Yu S., Chen J., Wu M., Chen H., Kato N., Yuan Z.;
RT "Hepatitis B virus polymerase inhibits RIG-I- and Toll-like receptor 3-
RT mediated beta interferon induction in human hepatocytes through
RT interference with interferon regulatory factor 3 activation and dampening
RT of the interaction between TBK1/IKKepsilon and DDX3.";
RL J. Gen. Virol. 91:2080-2090(2010).
RN [32]
RP INTERACTION WITH OPTN AND TRAF3.
RX PubMed=20174559; DOI=10.1371/journal.ppat.1000778;
RA Mankouri J., Fragkoudis R., Richards K.H., Wetherill L.F., Harris M.,
RA Kohl A., Elliott R.M., Macdonald A.;
RT "Optineurin negatively regulates the induction of IFNbeta in response to
RT RNA virus infection.";
RL PLoS Pathog. 6:E1000778-E1000778(2010).
RN [33]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [34]
RP INVOLVEMENT IN GLC1P, TISSUE SPECIFICITY, AND VARIANTS PHE-151; ILE-306 AND
RP ALA-464.
RX PubMed=21447600; DOI=10.1093/hmg/ddr123;
RA Fingert J.H., Robin A.L., Stone J.L., Roos B.R., Davis L.K., Scheetz T.E.,
RA Bennett S.R., Wassink T.H., Kwon Y.H., Alward W.L., Mullins R.F.,
RA Sheffield V.C., Stone E.M.;
RT "Copy number variations on chromosome 12q14 in patients with normal tension
RT glaucoma.";
RL Hum. Mol. Genet. 20:2482-2494(2011).
RN [35]
RP UBIQUITINATION BY MIB1.
RX PubMed=21903422; DOI=10.1016/j.immuni.2011.06.014;
RA Li S., Wang L., Berman M., Kong Y.Y., Dorf M.E.;
RT "Mapping a dynamic innate immunity protein interaction network regulating
RT type I interferon production.";
RL Immunity 35:426-440(2011).
RN [36]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH IFIT3 AND MAVS.
RX PubMed=21813773; DOI=10.4049/jimmunol.1100963;
RA Liu X.Y., Chen W., Wei B., Shan Y.F., Wang C.;
RT "IFN-induced TPR protein IFIT3 potentiates antiviral signaling by bridging
RT MAVS and TBK1.";
RL J. Immunol. 187:2559-2568(2011).
RN [37]
RP FUNCTION IN PHOSPHORYLATION OF VPS37C, AND CATALYTIC ACTIVITY.
RX PubMed=21270402; DOI=10.4049/jimmunol.1000262;
RA Da Q., Yang X., Xu Y., Gao G., Cheng G., Tang H.;
RT "TANK-binding kinase 1 attenuates PTAP-dependent retroviral budding through
RT targeting endosomal sorting complex required for transport-I.";
RL J. Immunol. 186:3023-3030(2011).
RN [38]
RP FUNCTION, INTERACTION WITH AZI2; TANK AND TBKBP1, AND MUTAGENESIS OF
RP ASP-135; MET-690; LEU-693; LYS-694; LEU-704; ASN-708 AND LEU-711.
RX PubMed=21931631; DOI=10.1371/journal.pone.0023971;
RA Goncalves A., Burckstummer T., Dixit E., Scheicher R., Gorna M.W.,
RA Karayel E., Sugar C., Stukalov A., Berg T., Kralovics R., Planyavsky M.,
RA Bennett K.L., Colinge J., Superti-Furga G.;
RT "Functional dissection of the TBK1 molecular network.";
RL PLoS ONE 6:E23971-E23971(2011).
RN [39]
RP FUNCTION IN PHOSPHORYLATION OF AKT1, AND CATALYTIC ACTIVITY.
RX PubMed=21464307; DOI=10.1073/pnas.1016132108;
RA Xie X., Zhang D., Zhao B., Lu M.K., You M., Condorelli G., Wang C.Y.,
RA Guan K.L.;
RT "IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct
RT phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:6474-6479(2011).
RN [40]
RP FUNCTION IN PHOSPHORYLATION OF OPTN, AND CATALYTIC ACTIVITY.
RX PubMed=21617041; DOI=10.1126/science.1205405;
RA Wild P., Farhan H., McEwan D.G., Wagner S., Rogov V.V., Brady N.R.,
RA Richter B., Korac J., Waidmann O., Choudhary C., Dotsch V., Bumann D.,
RA Dikic I.;
RT "Phosphorylation of the autophagy receptor optineurin restricts Salmonella
RT growth.";
RL Science 333:228-233(2011).
RN [41]
RP REVIEW ON FUNCTION, AND DOMAIN.
RX PubMed=21042276; DOI=10.1038/onc.2010.493;
RA Shen R.R., Hahn W.C.;
RT "Emerging roles for the non-canonical IKKs in cancer.";
RL Oncogene 30:631-641(2011).
RN [42]
RP FUNCTION, AND PHOSPHORYLATION BY IKBKB/IKKB.
RX PubMed=21138416; DOI=10.1042/bj20101701;
RA Clark K., Peggie M., Plater L., Sorcek R.J., Young E.R., Madwed J.B.,
RA Hough J., McIver E.G., Cohen P.;
RT "Novel cross-talk within the IKK family controls innate immunity.";
RL Biochem. J. 434:93-104(2011).
RN [43]
RP DEPHOSPHORYLATION AT SER-172.
RX PubMed=22750291; DOI=10.1016/j.cellsig.2012.06.017;
RA Zhao Y., Liang L., Fan Y., Sun S., An L., Shi Z., Cheng J., Jia W., Sun W.,
RA Mori-Akiyama Y., Zhang H., Fu S., Yang J.;
RT "PPM1B negatively regulates antiviral response via dephosphorylating
RT TBK1.";
RL Cell. Signal. 24:2197-2204(2012).
RN [44]
RP INVOLVEMENT IN GLC1P.
RX PubMed=22306015; DOI=10.1016/j.exer.2011.12.021;
RA Kawase K., Allingham R.R., Meguro A., Mizuki N., Roos B.,
RA Solivan-Timpe F.M., Robin A.L., Ritch R., Fingert J.H.;
RT "Confirmation of TBK1 duplication in normal tension glaucoma.";
RL Exp. Eye Res. 96:178-180(2012).
RN [45]
RP INVOLVEMENT IN IIAE8, VARIANTS IIAE8 ALA-50 AND ALA-159, CHARACTERIZATION
RP OF VARIANTS IIAE8 ALA-50 AND ALA-159, MUTAGENESIS OF LYS-38,
RP PHOSPHORYLATION AT SER-172, AND FUNCTION.
RX PubMed=22851595; DOI=10.1084/jem.20111316;
RA Herman M., Ciancanelli M., Ou Y.H., Lorenzo L., Klaudel-Dreszler M.,
RA Pauwels E., Sancho-Shimizu V., Perez de Diego R., Abhyankar A.,
RA Israelsson E., Guo Y., Cardon A., Rozenberg F., Lebon P., Tardieu M.,
RA Heropolitanska-Pliszka E., Chaussabel D., White M.A., Abel L., Zhang S.Y.,
RA Casanova J.L.;
RT "Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes
RT simplex encephalitis of childhood.";
RL J. Exp. Med. 209:1567-1582(2012).
RN [46]
RP UBIQUITINATION BY TRAIP.
RX PubMed=22945920; DOI=10.1084/jem.20120024;
RA Zhang M., Wang L., Zhao X., Zhao K., Meng H., Zhao W., Gao C.;
RT "TRAF-interacting protein (TRIP) negatively regulates IFN-beta production
RT and antiviral response by promoting proteasomal degradation of TANK-binding
RT kinase 1.";
RL J. Exp. Med. 209:1703-1711(2012).
RN [47]
RP UBIQUITINATION AT LYS-670 BY DTX4.
RX PubMed=22388039; DOI=10.1038/ni.2239;
RA Cui J., Li Y., Zhu L., Liu D., Songyang Z., Wang H.Y., Wang R.F.;
RT "NLRP4 negatively regulates type I interferon signaling by targeting the
RT kinase TBK1 for degradation via the ubiquitin ligase DTX4.";
RL Nat. Immunol. 13:387-395(2012).
RN [48]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-716, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [49]
RP INTERACTION WITH SFTSV NSS (MICROBIAL INFECTION).
RX PubMed=24478431; DOI=10.1128/jvi.03021-13;
RA Santiago F.W., Covaleda L.M., Sanchez-Aparicio M.T., Silvas J.A.,
RA Diaz-Vizarreta A.C., Patel J.R., Popov V., Yu X.J., Garcia-Sastre A.,
RA Aguilar P.V.;
RT "Hijacking of RIG-I signaling proteins into virus-induced cytoplasmic
RT structures correlates with the inhibition of type I interferon responses.";
RL J. Virol. 88:4572-4585(2014).
RN [50]
RP INTERACTION WITH SFTSV NSS (MICROBIAL INFECTION).
RX PubMed=24706939; DOI=10.1093/jmcb/mju015;
RA Ning Y.J., Wang M., Deng M., Shen S., Liu W., Cao W.C., Deng F., Wang Y.Y.,
RA Hu Z., Wang H.;
RT "Viral suppression of innate immunity via spatial isolation of
RT TBK1/IKKepsilon from mitochondrial antiviral platform.";
RL J. Mol. Cell Biol. 6:324-337(2014).
RN [51]
RP INVOLVEMENT IN FTDALS4, AND VARIANTS FTDALS4 ILE-306; GLU-401 AND LYS-696.
RX PubMed=25943890; DOI=10.1007/s00401-015-1436-x;
RA Pottier C., Bieniek K.F., Finch N., van de Vorst M., Baker M.,
RA Perkersen R., Brown P., Ravenscroft T., van Blitterswijk M.,
RA Nicholson A.M., DeTure M., Knopman D.S., Josephs K.A., Parisi J.E.,
RA Petersen R.C., Boylan K.B., Boeve B.F., Graff-Radford N.R., Veltman J.A.,
RA Gilissen C., Murray M.E., Dickson D.W., Rademakers R.;
RT "Whole-genome sequencing reveals important role for TBK1 and OPTN mutations
RT in frontotemporal lobar degeneration without motor neuron disease.";
RL Acta Neuropathol. 130:77-92(2015).
RN [52]
RP INTERACTION WITH TICAM1.
RX PubMed=25736436; DOI=10.15252/embr.201439637;
RA Hu Y.H., Zhang Y., Jiang L.Q., Wang S., Lei C.Q., Sun M.S., Shu H.B.,
RA Liu Y.;
RT "WDFY1 mediates TLR3/4 signaling by recruiting TRIF.";
RL EMBO Rep. 16:447-455(2015).
RN [53]
RP INVOLVEMENT IN IIAE8, AND VARIANT IIAE8 VAL-207.
RX PubMed=26513235; DOI=10.1038/gene.2015.46;
RA Moerk N., Kofod-Olsen E., Soerensen K.B., Bach E., Oerntoft T.F.,
RA Oestergaard L., Paludan S.R., Christiansen M., Mogensen T.H.;
RT "Mutations in the TLR3 signaling pathway and beyond in adult patients with
RT herpes simplex encephalitis.";
RL Genes Immun. 16:552-566(2015).
RN [54]
RP INVOLVEMENT IN FTDALS4, VARIANTS FTDALS4 HIS-47; CYS-105; THR-305; GLN-308;
RP GLN-357; ARG-559; VAL-571; VAL-598; GLU-643 DEL AND LYS-696, AND
RP CHARACTERIZATION OF VARIANTS FTDALS4 HIS-47; GLN-308; GLN-357; ARG-559 AND
RP LYS-696.
RX PubMed=25803835; DOI=10.1038/nn.4000;
RA Freischmidt A., Wieland T., Richter B., Ruf W., Schaeffer V., Mueller K.,
RA Marroquin N., Nordin F., Huebers A., Weydt P., Pinto S., Press R.,
RA Millecamps S., Molko N., Bernard E., Desnuelle C., Soriani M.H., Dorst J.,
RA Graf E., Nordstroem U., Feiler M.S., Putz S., Boeckers T.M., Meyer T.,
RA Winkler A.S., Winkelman J., de Carvalho M., Thal D.R., Otto M.,
RA Braennstroem T., Volk A.E., Kursula P., Danzer K.M., Lichtner P., Dikic I.,
RA Meitinger T., Ludolph A.C., Strom T.M., Andersen P.M., Weishaupt J.H.;
RT "Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal
RT dementia.";
RL Nat. Neurosci. 18:631-636(2015).
RN [55]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=25636800; DOI=10.1126/science.aaa2630;
RA Liu S., Cai X., Wu J., Cong Q., Chen X., Li T., Du F., Ren J., Wu Y.T.,
RA Grishin N.V., Chen Z.J.;
RT "Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF
RT induces IRF3 activation.";
RL Science 347:AAA2630-AAA2630(2015).
RN [56]
RP FUNCTION.
RX PubMed=27103069; DOI=10.15252/embj.201593350;
RA Sellier C., Campanari M.L., Julie Corbier C., Gaucherot A.,
RA Kolb-Cheynel I., Oulad-Abdelghani M., Ruffenach F., Page A., Ciura S.,
RA Kabashi E., Charlet-Berguerand N.;
RT "Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to
RT induce motor neuron dysfunction and cell death.";
RL EMBO J. 35:1276-1297(2016).
RN [57]
RP INTERACTION WITH TRIM26, AND FUNCTION.
RX PubMed=26611359; DOI=10.1093/jmcb/mjv068;
RA Ran Y., Zhang J., Liu L.L., Pan Z.Y., Nie Y., Zhang H.Y., Wang Y.Y.;
RT "Autoubiquitination of TRIM26 links TBK1 to NEMO in RLR-mediated innate
RT antiviral immune response.";
RL J. Mol. Cell Biol. 8:31-43(2016).
RN [58]
RP UBIQUITINATION BY RNF128.
RX PubMed=27776110; DOI=10.1038/ni.3588;
RA Song G., Liu B., Li Z., Wu H., Wang P., Zhao K., Jiang G., Zhang L.,
RA Gao C.;
RT "E3 ubiquitin ligase RNF128 promotes innate antiviral immunity through K63-
RT linked ubiquitination of TBK1.";
RL Nat. Immunol. 17:1342-1351(2016).
RN [59]
RP INTERACTION WITH TTLL12 AND MAVS.
RX PubMed=28011935; DOI=10.4049/jimmunol.1601194;
RA Ju L.G., Zhu Y., Lei P.J., Yan D., Zhu K., Wang X., Li Q.L., Li X.J.,
RA Chen J.W., Li L.Y., Wu M.;
RT "TTLL12 Inhibits the Activation of Cellular Antiviral Signaling through
RT Interaction with VISA/MAVS.";
RL J. Immunol. 198:1274-1284(2017).
RN [60]
RP INTERACTION WITH HEARTLAND VIRUS NSS (MICROBIAL INFECTION).
RX PubMed=28848048; DOI=10.1074/jbc.m117.805127;
RA Ning Y.J., Feng K., Min Y.Q., Deng F., Hu Z., Wang H.;
RT "Heartland virus NSs protein disrupts host defenses by blocking the TBK1
RT kinase-IRF3 transcription factor interaction and signaling required for
RT interferon induction.";
RL J. Biol. Chem. 292:16722-16733(2017).
RN [61]
RP INTERACTION WITH HEARTLAND VIRUS NSS (MICROBIAL INFECTION), INTERACTION
RP WITH SFTSV NSS (MICROBIAL INFECTION), AND PHOSPHORYLATION AT SER-172.
RX PubMed=28680969; DOI=10.1128/msphere.00234-17;
RA Rezelj V.V., Li P., Chaudhary V., Elliott R.M., Jin D.Y., Brennan B.;
RT "Differential Antagonism of Human Innate Immune Responses by Tick-Borne
RT Phlebovirus Nonstructural Proteins.";
RL MSphere 2:0-0(2017).
RN [62]
RP INTERACTION WITH TRIM23.
RX PubMed=28871090; DOI=10.1038/s41564-017-0017-2;
RA Sparrer K.M.J., Gableske S., Zurenski M.A., Parker Z.M., Full F.,
RA Baumgart G.J., Kato J., Pacheco-Rodriguez G., Liang C., Pornillos O.,
RA Moss J., Vaughan M., Gack M.U.;
RT "TRIM23 mediates virus-induced autophagy via activation of TBK1.";
RL Nat. Microbiol. 2:1543-1557(2017).
RN [63]
RP INTERACTION WITH HERPES SIMPLEX VIRUS 1 PROTEIN ICP34.5 (MICROBIAL
RP INFECTION).
RX PubMed=28904192; DOI=10.1128/jvi.01156-17;
RA Manivanh R., Mehrbach J., Knipe D.M., Leib D.A.;
RT "Role of Herpes Simplex Virus 1 gamma34.5 in the Regulation of IRF3
RT Signaling.";
RL J. Virol. 91:0-0(2017).
RN [64]
RP INTERACTION WITH ZIKA VIRUS NON-STRUCTURAL PROTEIN 1 AND NON-STRUCTURAL
RP PROTEIN 4B (MICROBIAL INFECTION).
RX PubMed=28373913; DOI=10.1038/celldisc.2017.6;
RA Wu Y., Liu Q., Zhou J., Xie W., Chen C., Wang Z., Yang H., Cui J.;
RT "Zika virus evades interferon-mediated antiviral response through the co-
RT operation of multiple nonstructural proteins in vitro.";
RL Cell Discov. 3:17006-17006(2017).
RN [65]
RP INTERACTION WITH CEP170.
RX PubMed=30354798; DOI=10.1091/mbc.e18-02-0115;
RA Baerenz F., Kschonsak Y.T., Meyer A., Jafarpour A., Lorenz H., Hoffmann I.;
RT "Ccdc61 controls centrosomal localization of Cep170 and is required for
RT spindle assembly and symmetry.";
RL Mol. Biol. Cell 29:3105-3118(2018).
RN [66]
RP INTERACTION WITH TTC4; IKBKE; AZI2 AND TANK, AND SUBCELLULAR LOCATION.
RX PubMed=29251827; DOI=10.1002/pmic.201700403;
RA Shang J., Xia T., Han Q.Q., Zhao X., Hu M.M., Shu H.B., Guo L.;
RT "Quantitative Proteomics Identified TTC4 as a TBK1 Interactor and a
RT Positive Regulator of SeV-Induced Innate Immunity.";
RL Proteomics 18:0-0(2018).
RN [67]
RP INTERACTION WITH SFTSV NSS (MICROBIAL INFECTION).
RX PubMed=30021900; DOI=10.1128/jvi.00706-18;
RA Moriyama M., Igarashi M., Koshiba T., Irie T., Takada A., Ichinohe T.;
RT "Two Conserved Amino Acids within the NSs of Severe Fever with
RT Thrombocytopenia Syndrome Phlebovirus Are Essential for Anti-interferon
RT Activity.";
RL J. Virol. 92:0-0(2018).
RN [68]
RP INTERACTION WITH HNRNPA2B1.
RX PubMed=31320558; DOI=10.1126/science.aav0758;
RA Wang L., Wen M., Cao X.;
RT "Nuclear hnRNPA2B1 initiates and amplifies the innate immune response to
RT DNA viruses.";
RL Science 0:0-0(2019).
RN [69]
RP INTERACTION WITH CYLD.
RX PubMed=32185393; DOI=10.1093/brain/awaa039;
RA Dobson-Stone C., Hallupp M., Shahheydari H., Ragagnin A.M.G.,
RA Chatterton Z., Carew-Jones F., Shepherd C.E., Stefen H., Paric E., Fath T.,
RA Thompson E.M., Blumbergs P., Short C.L., Field C.D., Panegyres P.K.,
RA Hecker J., Nicholson G., Shaw A.D., Fullerton J.M., Luty A.A.,
RA Schofield P.R., Brooks W.S., Rajan N., Bennett M.F., Bahlo M.,
RA Landers J.E., Piguet O., Hodges J.R., Halliday G.M., Topp S.D., Smith B.N.,
RA Shaw C.E., McCann E., Fifita J.A., Williams K.L., Atkin J.D., Blair I.P.,
RA Kwok J.B.;
RT "CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral
RT sclerosis.";
RL Brain 143:783-799(2020).
RN [70]
RP INTERACTION WITH SARS-COV-2 NON-STRUCTURAL PROTEIN 6 (MICROBIAL INFECTION),
RP AND INTERACTION WITH SARS-COV-2 HELICASE (MICROBIAL INFECTION).
RX PubMed=32979938; DOI=10.1016/j.celrep.2020.108234;
RA Xia H., Cao Z., Xie X., Zhang X., Chen J.Y., Wang H., Menachery V.D.,
RA Rajsbaum R., Shi P.Y.;
RT "Evasion of Type I Interferon by SARS-CoV-2.";
RL Cell Rep. 33:108234-108234(2020).
RN [71]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF LYS-38.
RX PubMed=31709703; DOI=10.15252/embr.201948317;
RA Herhaus L., Bhaskara R.M., Lystad A.H., Gestal-Mato U.,
RA Covarrubias-Pinto A., Bonn F., Simonsen A., Hummer G., Dikic I.;
RT "TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls
RT autophagosome shedding by ATG4 protease.";
RL EMBO Rep. 21:e48317-e48317(2020).
RN [72]
RP INTERACTION WITH TRIM14, AND FUNCTION.
RX PubMed=32404352; DOI=10.4049/jimmunol.1901511;
RA Hoffpauir C.T., Bell S.L., West K.O., Jing T., Wagner A.R., Torres-Odio S.,
RA Cox J.S., West A.P., Li P., Patrick K.L., Watson R.O.;
RT "TRIM14 Is a Key Regulator of the Type I IFN Response during Mycobacterium
RT tuberculosis Infection.";
RL J. Immunol. 205:153-167(2020).
RN [73]
RP INTERACTION WITH TRAF3IP3, AND UBIQUITINATION.
RX PubMed=32366851; DOI=10.1038/s41467-020-16014-0;
RA Deng M., Tam J.W., Wang L., Liang K., Li S., Zhang L., Guo H., Luo X.,
RA Zhang Y., Petrucelli A., Davis B.K., Conti B.J., June Brickey W., Ko C.C.,
RA Lei Y.L., Sun S., Ting J.P.;
RT "TRAF3IP3 negatively regulates cytosolic RNA induced anti-viral signaling
RT by promoting TBK1 K48 ubiquitination.";
RL Nat. Commun. 11:2193-2193(2020).
RN [74]
RP INTERACTION WITH SARS-COV-2 M PROTEIN (MICROBIAL INFECTION), FUNCTION, AND
RP UBIQUITINATION.
RX PubMed=34084167; DOI=10.3389/fimmu.2021.662989;
RA Sui L., Zhao Y., Wang W., Wu P., Wang Z., Yu Y., Hou Z., Tan G., Liu Q.;
RT "SARS-CoV-2 Membrane Protein Inhibits Type I Interferon Production Through
RT Ubiquitin-Mediated Degradation of TBK1.";
RL Front. Immunol. 12:662989-662989(2021).
RN [75]
RP INTERACTION WITH HUMAN CYTOMEGALOVIRUS PROTEIN UL35 (MICROBIAL INFECTION).
RX PubMed=32466380; DOI=10.3390/microorganisms8060790;
RA Fabits M., Goncalves Magalhaes V., Chan B., Girault V., Elbasani E.,
RA Rossetti E., Saeland E., Messerle M., Pichlmair A., Lisnic V.J.,
RA Brinkmann M.M.;
RT "The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition
RT Receptor-Mediated Type I IFN Transcription.";
RL Microorganisms 8:0-0(2020).
RN [76]
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 1-657 IN COMPLEX WITH INHIBITORS,
RP FUNCTION, ACTIVE SITE, HOMODIMER, UBIQUITINATION AT LYS-30 AND LYS-401, AND
RP MUTAGENESIS OF LYS-30; ASP-33; LYS-38; ASP-135; GLU-355; ARG-357; LYS-401;
RP ARG-547; TYR-577; GLU-580; ILE-582 AND LYS-589.
RX PubMed=23453971; DOI=10.1016/j.celrep.2013.01.034;
RA Larabi A., Devos J.M., Ng S.L., Nanao M.H., Round A., Maniatis T.,
RA Panne D.;
RT "Crystal structure and mechanism of activation of TANK-binding kinase 1.";
RL Cell Rep. 3:734-746(2013).
RN [77]
RP X-RAY CRYSTALLOGRAPHY (2.61 ANGSTROMS) OF 1-657 IN COMPLEX WITH INHIBITORS,
RP FUNCTION, ACTIVE SITE, AUTOPHOSPHORYLATION, HOMODIMER, INTERACTION WITH
RP AZI2, AND MUTAGENESIS OF LYS-38; ASP-135; SER-172; LEU-316; TYR-325;
RP GLU-355; GLU-448; HIS-459; ILE-466 AND PHE-470.
RX PubMed=23453972; DOI=10.1016/j.celrep.2013.01.033;
RA Tu D., Zhu Z., Zhou A.Y., Yun C.H., Lee K.E., Toms A.V., Li Y., Dunn G.P.,
RA Chan E., Thai T., Yang S., Ficarro S.B., Marto J.A., Jeon H., Hahn W.C.,
RA Barbie D.A., Eck M.J.;
RT "Structure and ubiquitination-dependent activation of TANK-binding kinase
RT 1.";
RL Cell Rep. 3:747-758(2013).
RN [78]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 1-657 IN COMPLEX WITH INHIBITORS,
RP FUNCTION, AND PHOSPHORYLATION AT SER-172.
RX PubMed=23746807; DOI=10.1016/j.str.2013.04.025;
RA Shu C., Sankaran B., Chaton C.T., Herr A.B., Mishra A., Peng J., Li P.;
RT "Structural insights into the functions of TBK1 in innate antimicrobial
RT immunity.";
RL Structure 21:1137-1148(2013).
RN [79]
RP STRUCTURE BY ELECTRON MICROSCOPY (3.3 ANGSTROMS) OF 1-729 OF MUTANT ASN-135
RP IN COMPLEX WITH STING1, FUNCTION, INTERACTION WITH STING1, ACTIVE SITE, AND
RP MUTAGENESIS OF TYR-577; ASN-578 AND GLN-581.
RX PubMed=30842653; DOI=10.1038/s41586-019-1000-2;
RA Zhang C., Shang G., Gui X., Zhang X., Bai X.C., Chen Z.J.;
RT "Structural basis of STING binding with and phosphorylation by TBK1.";
RL Nature 567:394-398(2019).
RN [80]
RP VARIANTS [LARGE SCALE ANALYSIS] GLN-271; GLU-291; HIS-296; ARG-410 AND
RP ALA-464.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [81]
RP VARIANTS SER-24; LEU-152; ALA-159; 308-ARG--LEU-729 DEL; GLN-384; SER-388;
RP THR-397; ILE-508; MET-522; THR-533; GLN-653 AND SER-659, CHARACTERIZATION
RP OF VARIANTS SER-24; LEU-152; ALA-159; 308-ARG--LEU-729 DEL; GLN-384;
RP SER-388; THR-397; ILE-508; MET-522; THR-533; GLN-653 AND SER-659, AND
RP FUNCTION.
RX PubMed=32972995; DOI=10.1126/science.abd4570;
RG COVID-STORM Clinicians;
RG COVID Clinicians;
RG Imagine COVID Group;
RG French COVID Cohort Study Group;
RG CoV-Contact Cohort;
RG Amsterdam UMC Covid-19 Biobank;
RG COVID Human Genetic Effort;
RG NIAID-USUHS/TAGC COVID Immunity Group;
RA Zhang Q., Bastard P., Liu Z., Le Pen J., Moncada-Velez M., Chen J.,
RA Ogishi M., Sabli I.K.D., Hodeib S., Korol C., Rosain J., Bilguvar K.,
RA Ye J., Bolze A., Bigio B., Yang R., Arias A.A., Zhou Q., Zhang Y.,
RA Onodi F., Korniotis S., Karpf L., Philippot Q., Chbihi M., Bonnet-Madin L.,
RA Dorgham K., Smith N., Schneider W.M., Razooky B.S., Hoffmann H.H.,
RA Michailidis E., Moens L., Han J.E., Lorenzo L., Bizien L., Meade P.,
RA Neehus A.L., Ugurbil A.C., Corneau A., Kerner G., Zhang P., Rapaport F.,
RA Seeleuthner Y., Manry J., Masson C., Schmitt Y., Schlueter A., Le Voyer T.,
RA Khan T., Li J., Fellay J., Roussel L., Shahrooei M., Alosaimi M.F.,
RA Mansouri D., Al-Saud H., Al-Mulla F., Almourfi F., Al-Muhsen S.Z.,
RA Alsohime F., Al Turki S., Hasanato R., van de Beek D., Biondi A.,
RA Bettini L.R., D'Angio' M., Bonfanti P., Imberti L., Sottini A., Paghera S.,
RA Quiros-Roldan E., Rossi C., Oler A.J., Tompkins M.F., Alba C.,
RA Vandernoot I., Goffard J.C., Smits G., Migeotte I., Haerynck F.,
RA Soler-Palacin P., Martin-Nalda A., Colobran R., Morange P.E., Keles S.,
RA Coelkesen F., Ozcelik T., Yasar K.K., Senoglu S., Karabela S.N.,
RA Rodriguez-Gallego C., Novelli G., Hraiech S., Tandjaoui-Lambiotte Y.,
RA Duval X., Laouenan C., Snow A.L., Dalgard C.L., Milner J.D., Vinh D.C.,
RA Mogensen T.H., Marr N., Spaan A.N., Boisson B., Boisson-Dupuis S.,
RA Bustamante J., Puel A., Ciancanelli M.J., Meyts I., Maniatis T.,
RA Soumelis V., Amara A., Nussenzweig M., Garcia-Sastre A., Krammer F.,
RA Pujol A., Duffy D., Lifton R.P., Zhang S.Y., Gorochov G., Beziat V.,
RA Jouanguy E., Sancho-Shimizu V., Rice C.M., Abel L., Notarangelo L.D.,
RA Cobat A., Su H.C., Casanova J.L.;
RT "Inborn errors of type I IFN immunity in patients with life-threatening
RT COVID-19.";
RL Science 370:0-0(2020).
CC -!- FUNCTION: Serine/threonine kinase that plays an essential role in
CC regulating inflammatory responses to foreign agents (PubMed:12692549,
CC PubMed:14703513, PubMed:18583960, PubMed:12702806, PubMed:15367631,
CC PubMed:10581243, PubMed:11839743, PubMed:15485837, PubMed:21138416,
CC PubMed:25636800, PubMed:23453971, PubMed:23453972, PubMed:23746807,
CC PubMed:26611359, PubMed:32404352). Following activation of toll-like
CC receptors by viral or bacterial components, associates with TRAF3 and
CC TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and
CC IRF7 as well as DDX3X (PubMed:12692549, PubMed:14703513,
CC PubMed:18583960, PubMed:12702806, PubMed:15367631, PubMed:25636800).
CC This activity allows subsequent homodimerization and nuclear
CC translocation of the IRFs leading to transcriptional activation of pro-
CC inflammatory and antiviral genes including IFNA and IFNB
CC (PubMed:12702806, PubMed:15367631, PubMed:25636800, PubMed:32972995).
CC In order to establish such an antiviral state, TBK1 form several
CC different complexes whose composition depends on the type of cell and
CC cellular stimuli (PubMed:23453971, PubMed:23453972, PubMed:23746807).
CC Plays a key role in IRF3 activation: acts by first phosphorylating
CC innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif,
CC leading to recruitment of IRF3, thereby licensing IRF3 for
CC phosphorylation by TBK1 (PubMed:25636800, PubMed:30842653).
CC Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes,
CC and then enters the nucleus to induce expression of interferons
CC (PubMed:25636800). Thus, several scaffolding molecules including FADD,
CC TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-
CC containing-complexes (PubMed:21931631). Under particular conditions,
CC functions as a NF-kappa-B effector by phosphorylating NF-kappa-B
CC inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the
CC nucleus (PubMed:10783893, PubMed:15489227). Restricts bacterial
CC proliferation by phosphorylating the autophagy receptor OPTN/Optineurin
CC on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial
CC autophagy (PubMed:21617041). Phosphorylates SMCR8 component of the
CC C9orf72-SMCR8 complex, promoting autophagosome maturation
CC (PubMed:27103069). Phosphorylates ATG8 proteins MAP1LC3C and GABARAPL2,
CC thereby preventing their delipidation and premature removal from
CC nascent autophagosomes (PubMed:31709703). Phosphorylates and activates
CC AKT1 (PubMed:21464307). Seems to play a role in energy balance
CC regulation by sustaining a state of chronic, low-grade inflammation in
CC obesity, wich leads to a negative impact on insulin sensitivity (By
CC similarity). Attenuates retroviral budding by phosphorylating the
CC endosomal sorting complex required for transport-I (ESCRT-I) subunit
CC VPS37C (PubMed:21270402). Phosphorylates Borna disease virus (BDV) P
CC protein (PubMed:16155125). Plays an essential role in the TLR3- and
CC IFN-dependent control of herpes virus HSV-1 and HSV-2 infections in the
CC central nervous system (PubMed:22851595).
CC {ECO:0000250|UniProtKB:Q9WUN2, ECO:0000269|PubMed:10581243,
CC ECO:0000269|PubMed:10783893, ECO:0000269|PubMed:11839743,
CC ECO:0000269|PubMed:12692549, ECO:0000269|PubMed:12702806,
CC ECO:0000269|PubMed:14703513, ECO:0000269|PubMed:15367631,
CC ECO:0000269|PubMed:15485837, ECO:0000269|PubMed:15489227,
CC ECO:0000269|PubMed:16155125, ECO:0000269|PubMed:18583960,
CC ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:21270402,
CC ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:21617041,
CC ECO:0000269|PubMed:21931631, ECO:0000269|PubMed:22851595,
CC ECO:0000269|PubMed:23453971, ECO:0000269|PubMed:23453972,
CC ECO:0000269|PubMed:23746807, ECO:0000269|PubMed:25636800,
CC ECO:0000269|PubMed:26611359, ECO:0000269|PubMed:27103069,
CC ECO:0000269|PubMed:30842653, ECO:0000269|PubMed:31709703,
CC ECO:0000269|PubMed:32972995}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000269|PubMed:10783893, ECO:0000269|PubMed:14703513,
CC ECO:0000269|PubMed:15367631, ECO:0000269|PubMed:18583960,
CC ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:21270402,
CC ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:21617041,
CC ECO:0000269|PubMed:25636800, ECO:0000269|PubMed:31709703};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:10783893,
CC ECO:0000269|PubMed:14703513, ECO:0000269|PubMed:15367631,
CC ECO:0000269|PubMed:18583960, ECO:0000269|PubMed:21138416,
CC ECO:0000269|PubMed:21270402, ECO:0000269|PubMed:21464307,
CC ECO:0000269|PubMed:21617041, ECO:0000269|PubMed:25636800};
CC -!- SUBUNIT: Homodimer (PubMed:21145761). Interacts with DDX3X, TIRAP and
CC TRAF2 (PubMed:10581243, PubMed:14530355). Part of a ternary complex
CC consisting of TANK, TRAF2 and TBK1 (PubMed:10581243). Interacts with
CC AZI2, TANK and TBKBP1; these interactions are mutually exclusive and
CC mediate TBK1 activation (PubMed:14560022, PubMed:21931631,
CC PubMed:23453972, PubMed:10581243, PubMed:29251827). Interacts with
CC GSK3B; this interaction promotes TBK1 self-association and
CC autophosphorylation (PubMed:21145761). Interacts with SIKE1; SIKE1 is
CC associated with TBK1 under physiological condition and dissociated from
CC TBK1 upon viral infection or TLR3 stimulation (PubMed:16281057).
CC Interacts with IRF3, leading to IRF3 phosphorylation (PubMed:14703513,
CC PubMed:25636800). Interacts with DDX58/RIG-I (PubMed:16281057).
CC Interacts with CYLD (PubMed:18636086, PubMed:32185393). Interacts with
CC OPTN and TRAF3 (PubMed:20174559). Interacts with SRC (PubMed:19419966).
CC Interacts with the exocyst complex subunit SEC5/EXOC2; this interaction
CC is sufficient to trigger TBK1 activity (PubMed:17018283). Interacts
CC with STING1, leading to STING1 phosphorylation (PubMed:19416887,
CC PubMed:25636800, PubMed:30842653). Interacts with IFIT3 (via N-
CC terminus) (PubMed:21813773). Interacts with MAVS; interaction only
CC takes place in the presence of IFIT3 and leads to MAVS phosphorylation
CC (PubMed:21813773, PubMed:25636800, PubMed:28011935). Interacts (via
CC protein kinase domain) with TTLL12 (via TTL domain); the interaction
CC prevents MAVS binding to TBK1 (PubMed:28011935). Interacts with TICAM1;
CC this interaction is enhanced in the presence of WDFY1 and leads to
CC TICAM1 phosphorylation (PubMed:14530355, PubMed:14739303,
CC PubMed:25736436, PubMed:25636800). Interacts with TRIM26
CC (PubMed:26611359). Interacts with TRIM23 (PubMed:28871090). Interacts
CC with TTC4 and IKBKE (PubMed:29251827). Interacts with HNRNPA2B1
CC (PubMed:31320558). Interacts with DDX3X (PubMed:20375222). Interacts
CC with TRIM14 (PubMed:32404352). Interacts with CEP170; efficient complex
CC formation may be dependent on the presence of CCDC61 (PubMed:30354798).
CC Interacts with TRAF3IP3 (PubMed:32366851). Interacts with HSP90AA1; the
CC interaction mediates TBK1 association with TOMM70 (PubMed:20628368).
CC {ECO:0000269|PubMed:10581243, ECO:0000269|PubMed:14530355,
CC ECO:0000269|PubMed:14560022, ECO:0000269|PubMed:14703513,
CC ECO:0000269|PubMed:14739303, ECO:0000269|PubMed:16281057,
CC ECO:0000269|PubMed:17018283, ECO:0000269|PubMed:18636086,
CC ECO:0000269|PubMed:19416887, ECO:0000269|PubMed:19419966,
CC ECO:0000269|PubMed:20174559, ECO:0000269|PubMed:20375222,
CC ECO:0000269|PubMed:20628368, ECO:0000269|PubMed:21145761,
CC ECO:0000269|PubMed:21813773, ECO:0000269|PubMed:21931631,
CC ECO:0000269|PubMed:23453972, ECO:0000269|PubMed:25636800,
CC ECO:0000269|PubMed:25736436, ECO:0000269|PubMed:26611359,
CC ECO:0000269|PubMed:28011935, ECO:0000269|PubMed:28871090,
CC ECO:0000269|PubMed:29251827, ECO:0000269|PubMed:30354798,
CC ECO:0000269|PubMed:30842653, ECO:0000269|PubMed:31320558,
CC ECO:0000269|PubMed:32185393, ECO:0000269|PubMed:32366851,
CC ECO:0000269|PubMed:32404352}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Borna disease virus (BDV)
CC P protein leading to its phosphorylation.
CC {ECO:0000269|PubMed:16155125}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Ebola virus protein VP35.
CC {ECO:0000269|PubMed:19153231}.
CC -!- SUBUNIT: (Microbial infection) Interacts with HCV NS3; this interaction
CC leads to inhibition of cellular antiviral response by blocking
CC necessary interactions between the TBK1 and its substrates IRF3 and
CC IRF7. {ECO:0000269|PubMed:15841462}.
CC -!- SUBUNIT: (Microbial infection) Interacts with herpes simplex virus 1
CC protein ICP34.5. {ECO:0000269|PubMed:28904192}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Zika virus non-structural
CC protein 1/NS1 and non-structural protein 4B/NS4B.
CC {ECO:0000269|PubMed:28373913}.
CC -!- SUBUNIT: (Microbial infection) Interacts with SARS-CoV-2 non-structural
CC protein 6; this interaction decreases IRF3 phosphorylation by 57%,
CC which leads to reduced IFN-beta (IFNB) production (PubMed:32979938).
CC Interacts with SARS-CoV-2 helicase; this interaction inhibits TBK1
CC phosphorylation and decreases IRF3 phosphorylation by 75%, which leads
CC to reduced IFN-beta production (PubMed:32979938). Interacts with SARS-
CC CoV-2 M protein; the interaction promotes TBK1 degradation via 'Lys-
CC 48'-linked ubiquitination (PubMed:34084167).
CC {ECO:0000269|PubMed:32979938, ECO:0000269|PubMed:34084167}.
CC -!- SUBUNIT: (Microbial infection) Interacts with human cytomegalovirus
CC protein UL35; this interaction inhibits type I interferon production.
CC {ECO:0000269|PubMed:32466380}.
CC -!- SUBUNIT: (Microbial infection) Interacts with heartland virus NSs; this
CC interaction antagonizes TBK1 phosphorylation and inhibits TBK1-IRF3
CC interaction and thus the establishment of an antiviral state.
CC {ECO:0000269|PubMed:28680969, ECO:0000269|PubMed:28848048}.
CC -!- SUBUNIT: (Microbial infection) Interacts (via N-terminus) with Severe
CC fever with thrombocytopenia virus (SFTSV) NSs; this interaction
CC antagonizes TBK1 phosphorylation and sequesters TBK1 in NSs-induced
CC cytoplasmic inclusion bodies thereby inhibiting the IFN responses.
CC {ECO:0000269|PubMed:24478431, ECO:0000269|PubMed:24706939,
CC ECO:0000269|PubMed:28680969, ECO:0000269|PubMed:30021900}.
CC -!- INTERACTION:
CC Q9UHD2; Q9UKV8: AGO2; NbExp=2; IntAct=EBI-356402, EBI-528269;
CC Q9UHD2; Q7Z3C6: ATG9A; NbExp=2; IntAct=EBI-356402, EBI-727146;
CC Q9UHD2; Q9H6S1: AZI2; NbExp=7; IntAct=EBI-356402, EBI-359973;
CC Q9UHD2; Q13137: CALCOCO2; NbExp=7; IntAct=EBI-356402, EBI-739580;
CC Q9UHD2; Q6DT37: CDC42BPG; NbExp=3; IntAct=EBI-356402, EBI-689124;
CC Q9UHD2; P08238: HSP90AB1; NbExp=2; IntAct=EBI-356402, EBI-352572;
CC Q9UHD2; Q9Y6W8: ICOS; NbExp=5; IntAct=EBI-356402, EBI-3922712;
CC Q9UHD2; Q14164: IKBKE; NbExp=5; IntAct=EBI-356402, EBI-307369;
CC Q9UHD2; Q9Y6K9: IKBKG; NbExp=4; IntAct=EBI-356402, EBI-81279;
CC Q9UHD2; Q14653: IRF3; NbExp=10; IntAct=EBI-356402, EBI-2650369;
CC Q9UHD2; Q92985: IRF7; NbExp=2; IntAct=EBI-356402, EBI-968267;
CC Q9UHD2; Q7Z434: MAVS; NbExp=6; IntAct=EBI-356402, EBI-995373;
CC Q9UHD2; Q86YT6: MIB1; NbExp=2; IntAct=EBI-356402, EBI-2129148;
CC Q9UHD2; Q96AX9: MIB2; NbExp=2; IntAct=EBI-356402, EBI-2130249;
CC Q9UHD2; Q9NVV4: MTPAP; NbExp=2; IntAct=EBI-356402, EBI-2556166;
CC Q9UHD2; Q96CV9: OPTN; NbExp=16; IntAct=EBI-356402, EBI-748974;
CC Q9UHD2; O14730: RIOK3; NbExp=3; IntAct=EBI-356402, EBI-1047061;
CC Q9UHD2; P42226: STAT6; NbExp=7; IntAct=EBI-356402, EBI-1186478;
CC Q9UHD2; Q86WV6: STING1; NbExp=9; IntAct=EBI-356402, EBI-2800345;
CC Q9UHD2; Q92844: TANK; NbExp=13; IntAct=EBI-356402, EBI-356349;
CC Q9UHD2; A7MCY6: TBKBP1; NbExp=9; IntAct=EBI-356402, EBI-359969;
CC Q9UHD2; Q8IUC6: TICAM1; NbExp=3; IntAct=EBI-356402, EBI-525995;
CC Q9UHD2; Q12933: TRAF2; NbExp=7; IntAct=EBI-356402, EBI-355744;
CC Q9UHD2; Q13114: TRAF3; NbExp=4; IntAct=EBI-356402, EBI-357631;
CC Q9UHD2; O95801: TTC4; NbExp=5; IntAct=EBI-356402, EBI-1050890;
CC Q9UHD2; P40222: TXLNA; NbExp=6; IntAct=EBI-356402, EBI-359793;
CC Q9UHD2; Q62167: Ddx3x; Xeno; NbExp=8; IntAct=EBI-356402, EBI-773173;
CC Q9UHD2; O41932: GAMMAHV.ORF11; Xeno; NbExp=4; IntAct=EBI-356402, EBI-9544132;
CC Q9UHD2; P0DTC5: M; Xeno; NbExp=10; IntAct=EBI-356402, EBI-25475853;
CC Q9UHD2; P59596: M; Xeno; NbExp=5; IntAct=EBI-356402, EBI-25487824;
CC Q9UHD2; PRO_0000449630 [P0DTD1]: rep; Xeno; NbExp=6; IntAct=EBI-356402, EBI-25475888;
CC Q9UHD2; Q60803: Traf3; Xeno; NbExp=2; IntAct=EBI-356402, EBI-520135;
CC Q9UHD2; Q8BHN1: Txlng; Xeno; NbExp=2; IntAct=EBI-356402, EBI-6116854;
CC Q9UHD2; Q05127: VP35; Xeno; NbExp=2; IntAct=EBI-356402, EBI-6148294;
CC Q9UHD2; I0DF37; Xeno; NbExp=3; IntAct=EBI-356402, EBI-9543922;
CC Q9UHD2; I6W9F2; Xeno; NbExp=6; IntAct=EBI-356402, EBI-9518472;
CC Q9UHD2; K7Y1A2; Xeno; NbExp=2; IntAct=EBI-356402, EBI-8788634;
CC Q9UHD2; PRO_0000037572 [P27958]; Xeno; NbExp=2; IntAct=EBI-356402, EBI-6919131;
CC Q9UHD2; PRO_0000037573 [P27958]; Xeno; NbExp=4; IntAct=EBI-356402, EBI-3649474;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15485837,
CC ECO:0000269|PubMed:21813773, ECO:0000269|PubMed:29251827}. Note=Upon
CC mitogen stimulation or triggering of the immune system, TBK1 is
CC recruited to the exocyst by EXOC2. {ECO:0000269|PubMed:17018283}.
CC -!- TISSUE SPECIFICITY: Ubiquitous with higher expression in testis.
CC Expressed in the ganglion cells, nerve fiber layer and microvasculature
CC of the retina. {ECO:0000269|PubMed:10783893,
CC ECO:0000269|PubMed:21447600}.
CC -!- DOMAIN: Comprises A N-terminal kinase domain, a ubiquitin-like domain
CC and a C-terminal coiled-coil region mediating homodimerization.
CC {ECO:0000269|PubMed:17599067, ECO:0000269|PubMed:21042276}.
CC -!- PTM: Autophosphorylation at Ser-172 activates the kinase, and is an
CC essential step for virus-triggered signaling. Phosphorylated by
CC IKBKB/IKKB at Ser-172. Phosphorylation requires homodimerization and
CC ubiquitination at Lys-30 and Lys-401. Dephosphorylated at Ser-172 by
CC PPM1B and this negatively regulates its role in mediating antiviral
CC response. {ECO:0000269|PubMed:11839743, ECO:0000269|PubMed:21138416,
CC ECO:0000269|PubMed:23453971, ECO:0000269|PubMed:23746807}.
CC -!- PTM: 'Lys-63'-linked polyubiquitination by MIB1 after RNA virus
CC infection, or by NRDP1 after LPS stimulation at Lys-30 and Lys-401,
CC participates in kinase activation. 'Lys-48'-linked polyubiquitination
CC at Lys-670 by DTX4 leads to proteasomal degradation. 'Lys-48'-linked
CC polyubiquitination by TRAIP also leads to proteasomal degradation.
CC 'Lys-63'-linked polyubiquitination by RNF128 at Lys-30 and Lys-401
CC leads to the activation of antiviral responses.
CC {ECO:0000269|PubMed:22388039, ECO:0000269|PubMed:23453971,
CC ECO:0000269|PubMed:27776110, ECO:0000269|PubMed:32366851}.
CC -!- PTM: (Microbial infection) Interaction with SARS-CoV-2 M protein
CC induces 'Lys-48'-linked ubiquitination which leads to proteasomal
CC degradation. {ECO:0000269|PubMed:34084167}.
CC -!- DISEASE: Glaucoma 1, open angle, P (GLC1P) [MIM:177700]: A form of
CC primary open angle glaucoma (POAG). POAG is characterized by a specific
CC pattern of optic nerve and visual field defects. The angle of the
CC anterior chamber of the eye is open, and usually the intraocular
CC pressure is increased. However, glaucoma can occur at any intraocular
CC pressure. The disease is generally asymptomatic until the late stages,
CC by which time significant and irreversible optic nerve damage has
CC already taken place. GLC1P is characterized by early onset, thin
CC central corneas and low intraocular pressure.
CC {ECO:0000269|PubMed:21447600, ECO:0000269|PubMed:22306015}. Note=The
CC disease may be caused by variants affecting the gene represented in
CC this entry. A copy number variation on chromosome 12q14 consisting of a
CC 300 kb duplication that includes TBK1, XPOT, RASSF3 and GNS has been
CC found in individuals affected by glaucoma. TBK1 is the most likely
CC candidate for the disorder (PubMed:21447600).
CC {ECO:0000269|PubMed:21447600}.
CC -!- DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 4
CC (FTDALS4) [MIM:616439]: A neurodegenerative disorder characterized by
CC frontotemporal dementia and/or amyotrophic lateral sclerosis in
CC affected individuals. There is high intrafamilial variation.
CC Frontotemporal dementia is characterized by frontal and temporal lobe
CC atrophy associated with neuronal loss, gliosis, and dementia. Patients
CC exhibit progressive changes in social, behavioral, and/or language
CC function. Amyotrophic lateral sclerosis is characterized by the death
CC of motor neurons in the brain, brainstem, and spinal cord, resulting in
CC fatal paralysis. {ECO:0000269|PubMed:25803835,
CC ECO:0000269|PubMed:25943890}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Encephalopathy, acute, infection-induced, 8, herpes-specific
CC (IIAE8) [MIM:617900]: A rare, often fatal complication of herpes
CC simplex infection, caused by virus spreading in the central nervous
CC system. Disease manifestations include low-grade fever, severe
CC headache, nausea, vomiting, and lethargy. Neurological features include
CC confusion, acute memory disturbances, disorientation, behavioral
CC changes, hemiparesis and seizures. {ECO:0000269|PubMed:22851595,
CC ECO:0000269|PubMed:26513235}. Note=Disease susceptibility is associated
CC with variants affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: In cancer cells, pathological TBK1 activation promotes
CC oncogenic transformation by suppressing programmed cell death.
CC Mechanistically, the RALB-SEC5/EXOC2-TBK1 signaling cascade seems to
CC participate in both innate immune signaling and cell transformation.
CC Additionally, TBK1 supports oncogenesis by directly phosphorylating and
CC activating AKT1 at the exocyst (PubMed:21042276).
CC {ECO:0000305|PubMed:21042276}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. I-kappa-B kinase subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA92129.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF191838; AAF05989.1; -; mRNA.
DR EMBL; AF174536; AAF69106.1; -; mRNA.
DR EMBL; AK002192; BAA92129.1; ALT_INIT; mRNA.
DR EMBL; AK291039; BAF83728.1; -; mRNA.
DR EMBL; CH471054; EAW97133.1; -; Genomic_DNA.
DR EMBL; BC034950; AAH34950.1; -; mRNA.
DR CCDS; CCDS8968.1; -.
DR RefSeq; NP_037386.1; NM_013254.3.
DR RefSeq; XP_005268866.1; XM_005268809.1.
DR RefSeq; XP_005268867.1; XM_005268810.1.
DR PDB; 4EFO; X-ray; 1.77 A; A/B=302-383.
DR PDB; 4EUT; X-ray; 2.60 A; A/B=2-385.
DR PDB; 4EUU; X-ray; 1.80 A; A/B=2-308.
DR PDB; 4IM0; X-ray; 2.40 A; A=1-657.
DR PDB; 4IM2; X-ray; 2.50 A; A=1-657.
DR PDB; 4IM3; X-ray; 3.34 A; A=1-657.
DR PDB; 4IW0; X-ray; 4.00 A; A=2-657.
DR PDB; 4IWO; X-ray; 2.61 A; A=2-657.
DR PDB; 4IWP; X-ray; 3.06 A; A=2-657.
DR PDB; 4IWQ; X-ray; 3.00 A; A=2-657.
DR PDB; 5EOA; X-ray; 2.50 A; C/D=677-729.
DR PDB; 5EOF; X-ray; 2.05 A; C/D=677-729.
DR PDB; 5EP6; X-ray; 1.45 A; B/D=677-729.
DR PDB; 5W5V; X-ray; 3.65 A; A=1-657.
DR PDB; 6BNY; X-ray; 3.34 A; A=1-657.
DR PDB; 6BOD; X-ray; 3.20 A; A=1-657.
DR PDB; 6BOE; X-ray; 3.60 A; A=1-657.
DR PDB; 6CQ0; X-ray; 3.19 A; A=1-657.
DR PDB; 6CQ4; X-ray; 3.20 A; A=1-657.
DR PDB; 6CQ5; X-ray; 3.35 A; A=1-657.
DR PDB; 6NT9; EM; 3.30 A; A/B=1-729.
DR PDB; 6O8B; X-ray; 3.40 A; A/B=2-657.
DR PDB; 6RSR; X-ray; 3.15 A; A=2-657.
DR PDB; 6RST; X-ray; 3.29 A; A=2-657.
DR PDB; 6RSU; X-ray; 2.75 A; A=2-657.
DR PDBsum; 4EFO; -.
DR PDBsum; 4EUT; -.
DR PDBsum; 4EUU; -.
DR PDBsum; 4IM0; -.
DR PDBsum; 4IM2; -.
DR PDBsum; 4IM3; -.
DR PDBsum; 4IW0; -.
DR PDBsum; 4IWO; -.
DR PDBsum; 4IWP; -.
DR PDBsum; 4IWQ; -.
DR PDBsum; 5EOA; -.
DR PDBsum; 5EOF; -.
DR PDBsum; 5EP6; -.
DR PDBsum; 5W5V; -.
DR PDBsum; 6BNY; -.
DR PDBsum; 6BOD; -.
DR PDBsum; 6BOE; -.
DR PDBsum; 6CQ0; -.
DR PDBsum; 6CQ4; -.
DR PDBsum; 6CQ5; -.
DR PDBsum; 6NT9; -.
DR PDBsum; 6O8B; -.
DR PDBsum; 6RSR; -.
DR PDBsum; 6RST; -.
DR PDBsum; 6RSU; -.
DR AlphaFoldDB; Q9UHD2; -.
DR SMR; Q9UHD2; -.
DR BioGRID; 118878; 280.
DR ComplexPortal; CPX-6018; STING-TRAF3-TBK1 complex.
DR ComplexPortal; CPX-6038; TBK1-IKKepsilon-NAP1 complex.
DR ComplexPortal; CPX-6089; TBK1-IKKepsilon-TANK complex.
DR ComplexPortal; CPX-6090; TBK1-IKKepsilon-SINTBAD complex.
DR CORUM; Q9UHD2; -.
DR DIP; DIP-27529N; -.
DR IntAct; Q9UHD2; 122.
DR MINT; Q9UHD2; -.
DR STRING; 9606.ENSP00000329967; -.
DR BindingDB; Q9UHD2; -.
DR ChEMBL; CHEMBL5408; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q9UHD2; -.
DR GuidetoPHARMACOLOGY; 2237; -.
DR iPTMnet; Q9UHD2; -.
DR MetOSite; Q9UHD2; -.
DR PhosphoSitePlus; Q9UHD2; -.
DR BioMuta; TBK1; -.
DR DMDM; 74761953; -.
DR CPTAC; CPTAC-910; -.
DR CPTAC; CPTAC-911; -.
DR EPD; Q9UHD2; -.
DR jPOST; Q9UHD2; -.
DR MassIVE; Q9UHD2; -.
DR MaxQB; Q9UHD2; -.
DR PaxDb; Q9UHD2; -.
DR PeptideAtlas; Q9UHD2; -.
DR PRIDE; Q9UHD2; -.
DR ProteomicsDB; 84323; -.
DR Antibodypedia; 16584; 629 antibodies from 46 providers.
DR DNASU; 29110; -.
DR Ensembl; ENST00000331710.10; ENSP00000329967.5; ENSG00000183735.11.
DR Ensembl; ENST00000650790.1; ENSP00000498995.1; ENSG00000183735.11.
DR GeneID; 29110; -.
DR KEGG; hsa:29110; -.
DR MANE-Select; ENST00000331710.10; ENSP00000329967.5; NM_013254.4; NP_037386.1.
DR UCSC; uc001ssc.3; human.
DR CTD; 29110; -.
DR DisGeNET; 29110; -.
DR GeneCards; TBK1; -.
DR HGNC; HGNC:11584; TBK1.
DR HPA; ENSG00000183735; Low tissue specificity.
DR MalaCards; TBK1; -.
DR MIM; 177700; phenotype.
DR MIM; 604834; gene.
DR MIM; 616439; phenotype.
DR MIM; 617900; phenotype.
DR neXtProt; NX_Q9UHD2; -.
DR OpenTargets; ENSG00000183735; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR Orphanet; 275872; Frontotemporal dementia with motor neuron disease.
DR Orphanet; 1930; Herpes simplex virus encephalitis.
DR PharmGKB; PA36348; -.
DR VEuPathDB; HostDB:ENSG00000183735; -.
DR eggNOG; KOG4250; Eukaryota.
DR GeneTree; ENSGT00950000182937; -.
DR HOGENOM; CLU_000288_101_1_1; -.
DR InParanoid; Q9UHD2; -.
DR OMA; DWSADMP; -.
DR OrthoDB; 563981at2759; -.
DR PhylomeDB; Q9UHD2; -.
DR TreeFam; TF324269; -.
DR PathwayCommons; Q9UHD2; -.
DR Reactome; R-HSA-1606341; IRF3 mediated activation of type 1 IFN.
DR Reactome; R-HSA-168928; DDX58/IFIH1-mediated induction of interferon-alpha/beta.
DR Reactome; R-HSA-3134975; Regulation of innate immune responses to cytosolic DNA.
DR Reactome; R-HSA-3249367; STAT6-mediated induction of chemokines.
DR Reactome; R-HSA-3270619; IRF3-mediated induction of type I IFN.
DR Reactome; R-HSA-9008059; Interleukin-37 signaling.
DR Reactome; R-HSA-9013973; TICAM1-dependent activation of IRF3/IRF7.
DR Reactome; R-HSA-918233; TRAF3-dependent IRF activation pathway.
DR Reactome; R-HSA-933541; TRAF6 mediated IRF7 activation.
DR Reactome; R-HSA-936440; Negative regulators of DDX58/IFIH1 signaling.
DR Reactome; R-HSA-936964; Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon.
DR Reactome; R-HSA-9679191; Potential therapeutics for SARS.
DR Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses.
DR SABIO-RK; Q9UHD2; -.
DR SignaLink; Q9UHD2; -.
DR SIGNOR; Q9UHD2; -.
DR BioGRID-ORCS; 29110; 31 hits in 1124 CRISPR screens.
DR ChiTaRS; TBK1; human.
DR GeneWiki; TANK-binding_kinase_1; -.
DR GenomeRNAi; 29110; -.
DR Pharos; Q9UHD2; Tchem.
DR PRO; PR:Q9UHD2; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q9UHD2; protein.
DR Bgee; ENSG00000183735; Expressed in colonic epithelium and 196 other tissues.
DR ExpressionAtlas; Q9UHD2; baseline and differential.
DR Genevisible; Q9UHD2; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:1902554; C:serine/threonine protein kinase complex; IC:ComplexPortal.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:0003676; F:nucleic acid binding; IEA:Ensembl.
DR GO; GO:0051219; F:phosphoprotein binding; IPI:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; NAS:ProtInc.
DR GO; GO:0019903; F:protein phosphatase binding; ISS:ARUK-UCL.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0002218; P:activation of innate immune response; IEA:Ensembl.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEA:Ensembl.
DR GO; GO:0051607; P:defense response to virus; IC:ComplexPortal.
DR GO; GO:0044565; P:dendritic cell proliferation; IEA:Ensembl.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; TAS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; TAS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IDA:UniProtKB.
DR GO; GO:0010629; P:negative regulation of gene expression; IEA:Ensembl.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:UniProtKB.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IDA:UniProtKB.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IEP:UniProtKB.
DR GO; GO:0032727; P:positive regulation of interferon-alpha production; IDA:BHF-UCL.
DR GO; GO:0032728; P:positive regulation of interferon-beta production; IDA:BHF-UCL.
DR GO; GO:0016239; P:positive regulation of macroautophagy; IDA:HGNC.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; NAS:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0032481; P:positive regulation of type I interferon production; TAS:UniProtKB.
DR GO; GO:0060340; P:positive regulation of type I interferon-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:1904417; P:positive regulation of xenophagy; IEA:Ensembl.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:1901214; P:regulation of neuron death; NAS:ParkinsonsUK-UCL.
DR GO; GO:0032479; P:regulation of type I interferon production; IDA:UniProtKB.
DR GO; GO:0009615; P:response to virus; TAS:UniProtKB.
DR GO; GO:0060337; P:type I interferon signaling pathway; IC:ComplexPortal.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR041309; TBK1_CCD1.
DR InterPro; IPR041087; TBK1_ULD.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF18394; TBK1_CCD1; 1.
DR Pfam; PF18396; TBK1_ULD; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amyotrophic lateral sclerosis; Antiviral defense;
KW ATP-binding; Coiled coil; Cytoplasm; Disease variant; Glaucoma;
KW Host-virus interaction; Immunity; Innate immunity; Isopeptide bond; Kinase;
KW Neurodegeneration; Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Ubl conjugation.
FT CHAIN 1..729
FT /note="Serine/threonine-protein kinase TBK1"
FT /id="PRO_0000086743"
FT DOMAIN 9..310
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 309..385
FT /note="Ubiquitin-like"
FT REGION 621..729
FT /note="Interaction with AZI2, TANK and TBKBP1"
FT /evidence="ECO:0000269|PubMed:21931631"
FT COILED 407..657
FT /evidence="ECO:0000250|UniProtKB:Q9WUN2"
FT COILED 658..713
FT /evidence="ECO:0000255"
FT ACT_SITE 135
FT /note="Proton acceptor"
FT /evidence="ECO:0000305|PubMed:23453971,
FT ECO:0000305|PubMed:23453972, ECO:0000305|PubMed:30842653"
FT BINDING 15..23
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 38
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000305"
FT MOD_RES 172
FT /note="Phosphoserine; by autocatalysis and IKKB"
FT /evidence="ECO:0000269|PubMed:11839743,
FT ECO:0000269|PubMed:22851595, ECO:0000269|PubMed:23746807"
FT MOD_RES 716
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT CROSSLNK 30
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23453971"
FT CROSSLNK 401
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23453971"
FT CROSSLNK 670
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:22388039"
FT VARIANT 24
FT /note="F -> S (loss of IFNB induction)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084111"
FT VARIANT 47
FT /note="R -> H (in FTDALS4; loss of kinase activity)"
FT /evidence="ECO:0000269|PubMed:25803835"
FT /id="VAR_073938"
FT VARIANT 50
FT /note="D -> A (in IIAE8; decreased expression levels;
FT dbSNP:rs1010930015)"
FT /evidence="ECO:0000269|PubMed:22851595"
FT /id="VAR_080517"
FT VARIANT 105
FT /note="Y -> C (in FTDALS4; dbSNP:rs1366668789)"
FT /evidence="ECO:0000269|PubMed:25803835"
FT /id="VAR_073939"
FT VARIANT 151
FT /note="S -> F (in dbSNP:rs55824172)"
FT /evidence="ECO:0000269|PubMed:21447600"
FT /id="VAR_069754"
FT VARIANT 152
FT /note="V -> L (no effect on IFNB induction)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084112"
FT VARIANT 159
FT /note="G -> A (in IIAE8; loss of kinase activity; loss of
FT autophosphorylation at S-172; loss of IFNB induction;
FT dbSNP:rs1555202947)"
FT /evidence="ECO:0000269|PubMed:22851595,
FT ECO:0000269|PubMed:32972995"
FT /id="VAR_080518"
FT VARIANT 207
FT /note="I -> V (in IIAE8; unknown pathological significance;
FT dbSNP:rs1555203557)"
FT /evidence="ECO:0000269|PubMed:26513235"
FT /id="VAR_080519"
FT VARIANT 271
FT /note="R -> Q (in dbSNP:rs56196591)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041208"
FT VARIANT 291
FT /note="K -> E (in dbSNP:rs34774243)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041209"
FT VARIANT 296
FT /note="D -> H (in a breast pleomorphic lobular carcinoma
FT sample; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041210"
FT VARIANT 305
FT /note="I -> T (in FTDALS4; dbSNP:rs770942184)"
FT /evidence="ECO:0000269|PubMed:25803835"
FT /id="VAR_073940"
FT VARIANT 306
FT /note="L -> I (in FTDALS4; unknown pathological
FT significance; dbSNP:rs201970436)"
FT /evidence="ECO:0000269|PubMed:21447600,
FT ECO:0000269|PubMed:25943890"
FT /id="VAR_069755"
FT VARIANT 308..729
FT /note="Missing (loss of IFNB induction)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084113"
FT VARIANT 308
FT /note="R -> Q (in FTDALS4; reduced kinase activity)"
FT /evidence="ECO:0000269|PubMed:25803835"
FT /id="VAR_073941"
FT VARIANT 357
FT /note="R -> Q (in FTDALS4; reduced kinase activity;
FT dbSNP:rs758357594)"
FT /evidence="ECO:0000269|PubMed:25803835"
FT /id="VAR_073942"
FT VARIANT 384
FT /note="R -> Q (no effect on IFNB induction)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084114"
FT VARIANT 388
FT /note="N -> D (in dbSNP:rs17857028)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_024746"
FT VARIANT 388
FT /note="N -> S (no effect on IFNB induction)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084115"
FT VARIANT 397
FT /note="I -> T (no effect on IFNB induction)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084116"
FT VARIANT 401
FT /note="K -> E (in FTDALS4; dbSNP:rs756751089)"
FT /evidence="ECO:0000269|PubMed:25943890"
FT /id="VAR_073943"
FT VARIANT 410
FT /note="G -> R (in a colorectal adenocarcinoma sample;
FT somatic mutation; dbSNP:rs1262765773)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041211"
FT VARIANT 464
FT /note="V -> A (in dbSNP:rs35635889)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:21447600"
FT /id="VAR_041212"
FT VARIANT 508
FT /note="L -> I (no effect on IFNB induction)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084117"
FT VARIANT 522
FT /note="I -> M (no effect on IFNB induction)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084118"
FT VARIANT 533
FT /note="A -> T (no effect on IFNB induction)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084119"
FT VARIANT 559
FT /note="M -> R (in FTDALS4; loss of kinase activity)"
FT /evidence="ECO:0000269|PubMed:25803835"
FT /id="VAR_073944"
FT VARIANT 570
FT /note="K -> Q (in dbSNP:rs17853341)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_024747"
FT VARIANT 571
FT /note="A -> V (in FTDALS4; dbSNP:rs765035140)"
FT /evidence="ECO:0000269|PubMed:25803835"
FT /id="VAR_073945"
FT VARIANT 598
FT /note="M -> V (in FTDALS4; dbSNP:rs899858451)"
FT /evidence="ECO:0000269|PubMed:25803835"
FT /id="VAR_073946"
FT VARIANT 643
FT /note="Missing (in FTDALS4)"
FT /evidence="ECO:0000269|PubMed:25803835"
FT /id="VAR_073947"
FT VARIANT 653
FT /note="E -> Q (no effect on IFNB induction)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084120"
FT VARIANT 659
FT /note="P -> S (no effect on IFNB induction)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084121"
FT VARIANT 696
FT /note="E -> K (in FTDALS4; loss of kinase activity; impairs
FT binding to OPTN; dbSNP:rs748112833)"
FT /evidence="ECO:0000269|PubMed:25803835,
FT ECO:0000269|PubMed:25943890"
FT /id="VAR_073948"
FT MUTAGEN 30
FT /note="K->R: Decreases ubiquitination. Abolishes
FT ubiquitination, phosphorylation and kinase activity; when
FT associated with R-401."
FT /evidence="ECO:0000269|PubMed:23453971"
FT MUTAGEN 33
FT /note="D->A: Decreases phosphorylation and kinase
FT activity."
FT /evidence="ECO:0000269|PubMed:23453971"
FT MUTAGEN 38
FT /note="K->A: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:10581243,
FT ECO:0000269|PubMed:22851595, ECO:0000269|PubMed:23453971,
FT ECO:0000269|PubMed:23453972, ECO:0000269|PubMed:31709703"
FT MUTAGEN 135
FT /note="D->N: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:21931631,
FT ECO:0000269|PubMed:23453971, ECO:0000269|PubMed:23453972,
FT ECO:0000269|PubMed:30842653"
FT MUTAGEN 172
FT /note="S->A: Loss of kinase activity. No effect on
FT dimerization."
FT /evidence="ECO:0000269|PubMed:11839743,
FT ECO:0000269|PubMed:23453972"
FT MUTAGEN 172
FT /note="S->E: Decreased kinase activity."
FT /evidence="ECO:0000269|PubMed:11839743,
FT ECO:0000269|PubMed:23453972"
FT MUTAGEN 316
FT /note="L->E: Decreases kinase activity. No effect on
FT phosphorylation."
FT /evidence="ECO:0000269|PubMed:23453972"
FT MUTAGEN 325
FT /note="Y->E: Abolishes phosphorylation and kinase
FT activity."
FT /evidence="ECO:0000269|PubMed:23453972"
FT MUTAGEN 355
FT /note="E->R: Decreases phosphorylation and kinase activity.
FT Abolishes dimerization; when associated with A-357 or R-
FT 448."
FT /evidence="ECO:0000269|PubMed:23453971,
FT ECO:0000269|PubMed:23453972"
FT MUTAGEN 357
FT /note="R->A: Decreases phosphorylation and kinase activity.
FT Abolishes dimerization; when associated with R-355."
FT /evidence="ECO:0000269|PubMed:23453971"
FT MUTAGEN 401
FT /note="K->R: Decreases ubiquitination. Abolishes
FT ubiquitination, phosphorylation and kinase activity; when
FT associated with R-30."
FT /evidence="ECO:0000269|PubMed:23453971"
FT MUTAGEN 448
FT /note="E->R: Decreases phosphorylation and kinase activity.
FT Abolishes dimerization; when associated with R-355."
FT /evidence="ECO:0000269|PubMed:23453972"
FT MUTAGEN 459
FT /note="H->E: Abolishes dimerization and decreases kinase
FT activity but no effect on phosphorylation; when associated
FT with E-466 and E-470."
FT /evidence="ECO:0000269|PubMed:23453972"
FT MUTAGEN 466
FT /note="I->E: Abolishes dimerization and decreases kinase
FT activity but no effect on phosphorylation; when associated
FT with E-459 and E-470."
FT /evidence="ECO:0000269|PubMed:23453972"
FT MUTAGEN 470
FT /note="F->E: Abolishes dimerization and decreases kinase
FT activity but no effect on phosphorylation; when associated
FT with E-459 and E-466."
FT /evidence="ECO:0000269|PubMed:23453972"
FT MUTAGEN 547
FT /note="R->D: Decreases phosphorylation and kinase activity.
FT Abolishes dimerization."
FT /evidence="ECO:0000269|PubMed:23453971"
FT MUTAGEN 577
FT /note="Y->A: Decreases kinase activity. Reduced
FT phosphorylation of STING1."
FT /evidence="ECO:0000269|PubMed:23453971,
FT ECO:0000269|PubMed:30842653"
FT MUTAGEN 578
FT /note="N->A: Reduced phosphorylation of STING1."
FT /evidence="ECO:0000269|PubMed:30842653"
FT MUTAGEN 580
FT /note="E->A: Decreases kinase activity."
FT /evidence="ECO:0000269|PubMed:23453971"
FT MUTAGEN 581
FT /note="Q->A: Reduced phosphorylation of STING1."
FT /evidence="ECO:0000269|PubMed:30842653"
FT MUTAGEN 582
FT /note="I->A: Decreases kinase activity."
FT /evidence="ECO:0000269|PubMed:23453971"
FT MUTAGEN 589
FT /note="K->D: Decreases phosphorylation and kinase
FT activity."
FT /evidence="ECO:0000269|PubMed:23453971"
FT MUTAGEN 690
FT /note="M->A: Decreases interaction with TANK."
FT /evidence="ECO:0000269|PubMed:21931631"
FT MUTAGEN 693
FT /note="L->A: Almost abolishes interaction with TANK."
FT /evidence="ECO:0000269|PubMed:21931631"
FT MUTAGEN 694
FT /note="K->E: Strongly decreases interaction with TANK and
FT TBKBP1. No effect on phosphorylation."
FT /evidence="ECO:0000269|PubMed:21931631"
FT MUTAGEN 704
FT /note="L->A: Strongly decreases interaction with AZI2, TANK
FT and TBKBP1. No effect on phosphorylation."
FT /evidence="ECO:0000269|PubMed:21931631"
FT MUTAGEN 708
FT /note="N->A: Decreases interaction with TANK."
FT /evidence="ECO:0000269|PubMed:21931631"
FT MUTAGEN 711
FT /note="L->A: Almost abolishes interaction with TANK."
FT /evidence="ECO:0000269|PubMed:21931631"
FT STRAND 1..3
FT /evidence="ECO:0007829|PDB:6CQ0"
FT STRAND 5..17
FT /evidence="ECO:0007829|PDB:4EUU"
FT STRAND 19..28
FT /evidence="ECO:0007829|PDB:4EUU"
FT TURN 29..31
FT /evidence="ECO:0007829|PDB:4EUU"
FT STRAND 34..40
FT /evidence="ECO:0007829|PDB:4EUU"
FT HELIX 42..46
FT /evidence="ECO:0007829|PDB:4EUU"
FT HELIX 49..61
FT /evidence="ECO:0007829|PDB:4EUU"
FT STRAND 65..67
FT /evidence="ECO:0007829|PDB:4IWO"
FT STRAND 70..75
FT /evidence="ECO:0007829|PDB:4EUU"
FT TURN 77..79
FT /evidence="ECO:0007829|PDB:4EUU"
FT STRAND 82..87
FT /evidence="ECO:0007829|PDB:4EUU"
FT HELIX 94..99
FT /evidence="ECO:0007829|PDB:4EUU"
FT HELIX 101..103
FT /evidence="ECO:0007829|PDB:4EUU"
FT HELIX 109..128
FT /evidence="ECO:0007829|PDB:4EUU"
FT HELIX 138..140
FT /evidence="ECO:0007829|PDB:4EUU"
FT STRAND 141..145
FT /evidence="ECO:0007829|PDB:4EUU"
FT STRAND 151..155
FT /evidence="ECO:0007829|PDB:4EUU"
FT TURN 161..163
FT /evidence="ECO:0007829|PDB:4IWQ"
FT HELIX 167..169
FT /evidence="ECO:0007829|PDB:4EUT"
FT STRAND 173..175
FT /evidence="ECO:0007829|PDB:4EUT"
FT HELIX 177..179
FT /evidence="ECO:0007829|PDB:4EUU"
FT HELIX 182..188
FT /evidence="ECO:0007829|PDB:4EUU"
FT HELIX 202..216
FT /evidence="ECO:0007829|PDB:4EUU"
FT STRAND 220..222
FT /evidence="ECO:0007829|PDB:4EUU"
FT HELIX 227..229
FT /evidence="ECO:0007829|PDB:4EUU"
FT HELIX 231..240
FT /evidence="ECO:0007829|PDB:4EUU"
FT STRAND 247..250
FT /evidence="ECO:0007829|PDB:4EUU"
FT STRAND 252..254
FT /evidence="ECO:0007829|PDB:6NT9"
FT STRAND 257..262
FT /evidence="ECO:0007829|PDB:4EUU"
FT HELIX 271..284
FT /evidence="ECO:0007829|PDB:4EUU"
FT STRAND 285..287
FT /evidence="ECO:0007829|PDB:4IWP"
FT TURN 289..291
FT /evidence="ECO:0007829|PDB:4EUU"
FT HELIX 305..307
FT /evidence="ECO:0007829|PDB:4EFO"
FT STRAND 308..315
FT /evidence="ECO:0007829|PDB:4EFO"
FT TURN 316..319
FT /evidence="ECO:0007829|PDB:4EFO"
FT STRAND 320..327
FT /evidence="ECO:0007829|PDB:4EFO"
FT HELIX 332..343
FT /evidence="ECO:0007829|PDB:4EFO"
FT HELIX 347..349
FT /evidence="ECO:0007829|PDB:4EFO"
FT STRAND 350..354
FT /evidence="ECO:0007829|PDB:4EFO"
FT STRAND 357..359
FT /evidence="ECO:0007829|PDB:4EFO"
FT HELIX 367..369
FT /evidence="ECO:0007829|PDB:4EFO"
FT STRAND 375..377
FT /evidence="ECO:0007829|PDB:4IM0"
FT STRAND 379..383
FT /evidence="ECO:0007829|PDB:4EFO"
FT HELIX 408..480
FT /evidence="ECO:0007829|PDB:4IM0"
FT HELIX 498..526
FT /evidence="ECO:0007829|PDB:4IM0"
FT TURN 527..529
FT /evidence="ECO:0007829|PDB:6RSU"
FT STRAND 530..532
FT /evidence="ECO:0007829|PDB:4IWO"
FT HELIX 535..539
FT /evidence="ECO:0007829|PDB:4IM0"
FT HELIX 544..546
FT /evidence="ECO:0007829|PDB:4IM0"
FT HELIX 548..571
FT /evidence="ECO:0007829|PDB:4IM0"
FT STRAND 572..574
FT /evidence="ECO:0007829|PDB:6O8B"
FT HELIX 577..603
FT /evidence="ECO:0007829|PDB:4IM0"
FT HELIX 605..647
FT /evidence="ECO:0007829|PDB:4IM0"
FT TURN 648..651
FT /evidence="ECO:0007829|PDB:4IM0"
FT HELIX 680..714
FT /evidence="ECO:0007829|PDB:5EP6"
FT STRAND 715..717
FT /evidence="ECO:0007829|PDB:5EP6"
SQ SEQUENCE 729 AA; 83642 MW; B58E4FE1B502276D CRC64;
MQSTSNHLWL LSDILGQGAT ANVFRGRHKK TGDLFAIKVF NNISFLRPVD VQMREFEVLK
KLNHKNIVKL FAIEEETTTR HKVLIMEFCP CGSLYTVLEE PSNAYGLPES EFLIVLRDVV
GGMNHLRENG IVHRDIKPGN IMRVIGEDGQ SVYKLTDFGA ARELEDDEQF VSLYGTEEYL
HPDMYERAVL RKDHQKKYGA TVDLWSIGVT FYHAATGSLP FRPFEGPRRN KEVMYKIITG
KPSGAISGVQ KAENGPIDWS GDMPVSCSLS RGLQVLLTPV LANILEADQE KCWGFDQFFA
ETSDILHRMV IHVFSLQQMT AHKIYIHSYN TATIFHELVY KQTKIISSNQ ELIYEGRRLV
LEPGRLAQHF PKTTEENPIF VVSREPLNTI GLIYEKISLP KVHPRYDLDG DASMAKAITG
VVCYACRIAS TLLLYQELMR KGIRWLIELI KDDYNETVHK KTEVVITLDF CIRNIEKTVK
VYEKLMKINL EAAELGEISD IHTKLLRLSS SQGTIETSLQ DIDSRLSPGG SLADAWAHQE
GTHPKDRNVE KLQVLLNCMT EIYYQFKKDK AERRLAYNEE QIHKFDKQKL YYHATKAMTH
FTDECVKKYE AFLNKSEEWI RKMLHLRKQL LSLTNQCFDI EEEVSKYQEY TNELQETLPQ
KMFTASSGIK HTMTPIYPSS NTLVEMTLGM KKLKEEMEGV VKELAENNHI LERFGSLTMD
GGLRNVDCL
