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 27-MAR-2024, entry version 207. 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 RIGI. 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 INTERACTION WITH HUMAN HERPESVIRUS 1 PROTEIN ICP34.5 (MICROBIAL INFECTION). RX PubMed=19010780; DOI=10.1074/jbc.m805905200; RA Verpooten D., Ma Y., Hou S., Yan Z., He B.; RT "Control of TANK-binding kinase 1-mediated signaling by the gamma(1)34.5 RT protein of herpes simplex virus 1."; RL J. Biol. Chem. 284:1097-1105(2009). RN [44] 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 [45] 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 [46] 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 [47] 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 [48] 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 [49] 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 [50] 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 [51] 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 [52] 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 [53] 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 [54] 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 [55] 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 [56] 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 [57] RP FUNCTION, SUBCELLULAR LOCATION, UBIQUITINATION AT LYS-670, AND MUTAGENESIS RP OF SER-172 AND LYS-670. RX PubMed=27692986; DOI=10.1016/j.molcel.2016.08.029; RA Lin M., Zhao Z., Yang Z., Meng Q., Tan P., Xie W., Qin Y., Wang R.F., RA Cui J.; RT "USP38 Inhibits Type I Interferon Signaling by Editing TBK1 Ubiquitination RT through NLRP4 Signalosome."; RL Mol. Cell 64:267-281(2016). RN [58] 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 [59] 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 [60] 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 [61] 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 [62] 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 [63] 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 [64] 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 [65] RP INTERACTION WITH HUMAN HERPESVIRUS 1 PROTEIN ICP34.5 (MICROBIAL 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 [66] 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 [67] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF LYS-38. RX PubMed=29150432; DOI=10.15252/embj.201696164; RA Bodur C., Kazyken D., Huang K., Ekim Ustunel B., Siroky K.A., Tooley A.S., RA Gonzalez I.E., Foley D.H., Acosta-Jaquez H.A., Barnes T.M., Steinl G.K., RA Cho K.W., Lumeng C.N., Riddle S.M., Myers M.G. Jr., Fingar D.C.; RT "The IKK-related kinase TBK1 activates mTORC1 directly in response to RT growth factors and innate immune agonists."; RL EMBO J. 37:19-38(2018). RN [68] 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 [69] 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 [70] 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 [71] 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 [72] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF LYS-38. RX PubMed=31530866; DOI=10.1038/s41598-019-49707-8; RA Antonia R.J., Castillo J., Herring L.E., Serafin D.S., Liu P., Graves L.M., RA Baldwin A.S., Hagan R.S.; RT "TBK1 limits mTORC1 by promoting phosphorylation of Raptor Ser877."; RL Sci. Rep. 9:13470-13470(2019). RN [73] 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 [74] 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 [75] 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 [76] 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 [77] RP INTERACTION WITH TAX1BP1. RX PubMed=33226137; DOI=10.15252/embj.2020104948; RA Ohnstad A.E., Delgado J.M., North B.J., Nasa I., Kettenbach A.N., RA Schultz S.W., Shoemaker C.J.; RT "Receptor-mediated clustering of FIP200 bypasses the role of LC3 lipidation RT in autophagy."; RL EMBO J. 39:e104948-e104948(2020). RN [78] 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 [79] 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 [80] 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 [81] RP UBIQUITINATION BY TRAF7. RX PubMed=37086853; DOI=10.1016/j.virs.2023.04.005; RA Huang J.P., Yang Y.X., Chen T., Wang D.D., Li J., Xu L.G.; RT "TRAF7 negatively regulates the RLR signaling pathway by facilitating the RT K48-linked ubiquitination of TBK1."; RL Virol. Sin. 38:419-428(2023). RN [82] RP DEUBIQUITINATION BY EPSTEIN-BARR VIRUS PROTEIN BPLF1 (MICROBIAL INFECTION). RX PubMed=36802409; DOI=10.1371/journal.ppat.1011186; RA Lui W.Y., Bharti A., Wong N.M., Jangra S., Botelho M.G., Yuen K.S., RA Jin D.Y.; RT "Suppression of cGAS- and RIG-I-mediated innate immune signaling by RT Epstein-Barr virus deubiquitinase BPLF1."; RL PLoS Pathog. 19:e1011186-e1011186(2023). RN [83] 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 [84] 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 [85] 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 [86] 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 [87] 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 [88] 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). Acts both as a positive and CC negative regulator of the mTORC1 complex, depending on the context: CC activates mTORC1 in response to growth factors by catalyzing CC phosphorylation of MTOR, while it limits the mTORC1 complex by CC promoting phosphorylation of RPTOR (PubMed:29150432, PubMed:31530866). 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:29150432, ECO:0000269|PubMed:30842653, CC ECO:0000269|PubMed:31530866, 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:29150432, CC ECO:0000269|PubMed:31530866, 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 RIGI (PubMed:16281057). Interacts with CC CYLD (PubMed:18636086, PubMed:32185393). Interacts with OPTN and TRAF3 CC (PubMed:20174559). Interacts with SRC (PubMed:19419966). Interacts with CC the exocyst complex subunit SEC5/EXOC2; this interaction is sufficient CC to trigger TBK1 activity (PubMed:17018283). Interacts with STING1, CC leading to STING1 phosphorylation (PubMed:19416887, PubMed:25636800, CC PubMed:30842653). Interacts with IFIT3 (via N-terminus) CC (PubMed:21813773). Interacts with MAVS; interaction only takes place in CC 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 Interacts with TAX1BP1 (PubMed:33226137). {ECO:0000269|PubMed:10581243, CC ECO:0000269|PubMed:14530355, ECO:0000269|PubMed:14560022, CC ECO:0000269|PubMed:14703513, ECO:0000269|PubMed:14739303, CC ECO:0000269|PubMed:16281057, ECO:0000269|PubMed:17018283, CC ECO:0000269|PubMed:18636086, ECO:0000269|PubMed:19416887, CC ECO:0000269|PubMed:19419966, ECO:0000269|PubMed:20174559, CC ECO:0000269|PubMed:20375222, ECO:0000269|PubMed:20628368, CC ECO:0000269|PubMed:21145761, ECO:0000269|PubMed:21813773, CC ECO:0000269|PubMed:21931631, ECO:0000269|PubMed:23453972, CC ECO:0000269|PubMed:25636800, ECO:0000269|PubMed:25736436, CC ECO:0000269|PubMed:26611359, ECO:0000269|PubMed:28011935, CC ECO:0000269|PubMed:28871090, ECO:0000269|PubMed:29251827, CC ECO:0000269|PubMed:30354798, ECO:0000269|PubMed:30842653, CC ECO:0000269|PubMed:31320558, ECO:0000269|PubMed:32185393, CC ECO:0000269|PubMed:32366851, ECO:0000269|PubMed:32404352, CC ECO:0000269|PubMed:33226137}. 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 human herpesvirus 1 CC protein ICP34.5. {ECO:0000269|PubMed:19010780, CC 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; Q9H492: MAP1LC3A; NbExp=2; IntAct=EBI-356402, EBI-720768; CC Q9UHD2; Q9GZQ8: MAP1LC3B; NbExp=2; IntAct=EBI-356402, EBI-373144; 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; W5VXH5: NSs; Xeno; NbExp=3; IntAct=EBI-356402, EBI-9543922; 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; 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-48'-linked polyubiquitination by TRAF7; leading to proteasomal CC degradation (PubMed:37086853). 'Lys-63'-linked polyubiquitination by CC RNF128 at Lys-30 and Lys-401 leads to the activation of antiviral CC responses. 'Lys-48'-linked polyubiquitination after 'lys-33'-linked CC deubiquitination by USP38 promotes TBK1 degradation (PubMed:27692986). CC {ECO:0000269|PubMed:22388039, ECO:0000269|PubMed:23453971, CC ECO:0000269|PubMed:27692986, ECO:0000269|PubMed:27776110, CC ECO:0000269|PubMed:32366851, ECO:0000269|PubMed:37086853}. 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 -!- PTM: (Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1 CC on both 'Lys-48' and 'Lys-63'-linked ubiquitin chains; leading to CC inhibition of type I interfewron production. CC {ECO:0000269|PubMed:36802409}. 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}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 EMDB; EMD-0506; -. DR SMR; Q9UHD2; -. DR BioGRID; 118878; 409. 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; 127. 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-2972; -. DR CPTAC; CPTAC-2973; -. DR CPTAC; CPTAC-910; -. DR CPTAC; CPTAC-911; -. DR EPD; Q9UHD2; -. DR jPOST; Q9UHD2; -. DR MassIVE; Q9UHD2; -. DR MaxQB; Q9UHD2; -. DR PaxDb; 9606-ENSP00000329967; -. DR PeptideAtlas; Q9UHD2; -. DR ProteomicsDB; 84323; -. DR Pumba; Q9UHD2; -. DR Antibodypedia; 16584; 702 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 AGR; HGNC:11584; -. 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; WSADMPV; -. DR OrthoDB; 2957757at2759; -. 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-5357786; TNFR1-induced proapoptotic signaling. DR Reactome; R-HSA-5357905; Regulation of TNFR1 signaling. 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, IKBKE. DR Reactome; R-HSA-9679191; Potential therapeutics for SARS. DR Reactome; R-HSA-9692916; SARS-CoV-1 activates/modulates innate immune responses. 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; 34 hits in 1203 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 198 other cell types or tissues. DR ExpressionAtlas; Q9UHD2; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProt. 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; NAS: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; IDA:UniProt. DR GO; GO:0140374; P:antiviral innate immune response; IDA:UniProt. DR GO; GO:0007249; P:canonical NF-kappaB signal transduction; TAS:UniProtKB. DR GO; GO:0002753; P:cytoplasmic pattern recognition receptor signaling pathway; IDA:UniProt. DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEA:Ensembl. DR GO; GO:0051607; P:defense response to virus; NAS:ComplexPortal. DR GO; GO:0044565; P:dendritic cell proliferation; IEA:Ensembl. 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:1904262; P:negative regulation of TORC1 signaling; IDA:UniProtKB. DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:UniProtKB. DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IDA:UniProtKB. DR GO; GO:0010508; P:positive regulation of autophagy; IDA:UniProt. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; 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:1904263; P:positive regulation of TORC1 signaling; IDA:UniProtKB. 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; IDA:UniProt. 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:0032479; P:regulation of type I interferon production; IDA:UniProtKB. DR GO; GO:0009615; P:response to virus; TAS:UniProtKB. DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IDA:UniProt. DR GO; GO:0060337; P:type I interferon-mediated signaling pathway; NAS:ComplexPortal. DR CDD; cd13988; STKc_TBK1; 1. DR CDD; cd21954; TBK1_C; 1. DR CDD; cd17127; Ubl_TBK1; 1. DR Gene3D; 1.20.1270.420; -; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. 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 PANTHER; PTHR22969; IKB KINASE; 1. DR PANTHER; PTHR22969:SF14; SERINE_THREONINE-PROTEIN KINASE TBK1; 1. 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; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR Genevisible; Q9UHD2; HS. 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 ECO:0000269|PubMed:27692986" 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; uncertain 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; uncertain significance; FT 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:29150432, FT ECO:0000269|PubMed:31530866, 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. Loss of USP38-mediated degradation." FT /evidence="ECO:0000269|PubMed:11839743, FT ECO:0000269|PubMed:23453972, ECO:0000269|PubMed:27692986" 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 FT R-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 670 FT /note="K->R: Abrogates both 'Lys-48'-linked and FT 'Lys-33'-linked ubiquitination." FT /evidence="ECO:0000269|PubMed:27692986" 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 //