Journal of Shandong University (Health Sciences) ›› 2026, Vol. 64 ›› Issue (10): 36-53.doi: 10.6040/j.issn.1671-7554.0.2026.1154
DU Jie, LI Chaoqun, JIA Mutian
CLC Number:
| [1] Tojima Y, Fujimoto A, Delhase M, et al. NAK is an IkappaB kinase-activating kinase[J]. Nature, 2000, 404(6779): 778-782. [2] Pomerantz J L,Baltimore D. NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase[J]. EMBO J, 1999, 18(23): 6694-6704. [3] Chau T L, Gioia R, Gatot J S, et al. Are the IKKs and IKK-related kinases TBK1 and IKK-epsilon similarly activated?[J]. Trends Biochem Sci, 2008, 33(4): 171-180. [4] Clement J F, Meloche S.Servant M J. The IKK-related kinases: from innate immunity to oncogenesis[J]. Cell Res, 2008, 18(9): 889-899. [5] Sun Y, Revach O Y, Anderson S, et al. Targeting TBK1 to overcome resistance to cancer immunotherapy[J]. Nature, 2023, 615(7950): 158-167. [6] Fitzgerald K A, McWhirter S M, Faia K L, et al. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway[J]. Nat Immunol, 2003, 4(5): 491-496. [7] Takeuchi O,Akira S. Innate immunity to virus infection[J]. Immunol Rev, 2009, 227(1): 75-86. [8] Zhao W. Negative regulation of TBK1-mediated antiviral immunity[J]. FEBS Lett, 2013, 587(6): 542-548. [9] Decout A, Katz J D, Venkatraman S, et al. The cGAS-STING pathway as a therapeutic target in inflammatory diseases[J]. Nat Rev Immunol, 2021, 21(9): 548-569. [10] Hui L, Chen X, Huang M, et al. TANK-binding kinase 1 in the pathogenesis and treatment of inflammation-related diseases[J]. Int J Mol Sci, 2025, 26(5):1941. DOI: 10.3390/ijms26051941 [11] Wild P, Farhan H, McEwan D G, et al. Phosphorylation of the autophagy receptor optineurin restricts salmonella growth[J]. Science, 2011, 333(6039): 228-233. [12] Lazarou M, Sliter D A, Kane L A, et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy[J]. Nature, 2015, 524(7565): 309-314. [13] Zhao P, Wong K I, Sun X, et al. TBK1 at the crossroads of inflammation and energy homeostasis in adipose tissue[J]. Cell, 2018, 172(4): 731-743. [14] Reilly S M, Chiang S H, Decker S J, et al. An inhibitor of the protein kinases TBK1 and IKK-varepsilon improves obesity-related metabolic dysfunctions in mice[J]. Nat Med, 2013, 19(3): 313-321. [15] Calay E S,Hotamisligil G S. Turning off the inflammat-ory, but not the metabolic, flames[J]. Nat Med, 2013, 19(3): 265-267. [16] Barbie D A, Tamayo P, Boehm J S, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1[J]. Nature, 2009, 462(7269): 108-112. [17] Kim H J, Kim H J, Kim S Y, et al. TBK1 is a signaling hub in coordinating stress-adaptive mechanisms in head and neck cancer progression[J]. Autophagy, 2025, 21(8): 1744-1766. [18] Zhou D, Yao Y, Zong L, et al. TBK1 facilitates GLUT1-dependent glucose consumption by suppressing mTORC1 signaling in colorectal cancer progression[J]. Int J Biol Sci, 2022, 18(8): 3374-3389. [19] Li W, Guo F, Zeng R, et al. CDK4/6 alters TBK1 phosphorylation to inhibit the STING signaling pathway in prostate cancer[J]. Cancer Res, 2024, 84(16): 2588-2606. [20] Miranda A, Shirley C A, Jenkins R W. Emerging roles of TBK1 in cancer immunobiology[J]. Trends Cancer, 2024, 10(6): 531-540. [21] Tu D, Zhu Z, Zhou A Y, et al. Structure and ubiquitination-dependent activation of TANK-binding kinase 1[J]. Cell Rep, 2013, 3(3): 747-758. [22] 徐赫男, 李新宇, 方敏, 等. TANK结合激酶1在固有免疫应答中的作用及其泛素化调控[J]. 生物工程学报, 2021, 37(4): 1189-1204. Xu Henan, Li Xinyu, Fang Min, et al. Biological functions and ubiquitin modification of TBK1 in innate immunity[J]. Chinese Journal of Biotechnology, 2021, 37(4):1189-1204. [23] Zhao C, Zhao W. TANK-binding kinase 1 as a novel therapeutic target for viral diseases[J]. Expert Opin Ther Targets, 2019, 23(5): 437-446. [24] Zhang C, Shang G, Gui X, et al. Structural basis of STING binding with and phosphorylation by TBK1[J]. Nature, 2019, 567(7748): 394-398. [25] Li J, Li J, Miyahira A, et al. Crystal structure of the ubiquitin-like domain of human TBK1[J]. Protein Cell, 2012, 3(5): 383-391. [26] Ma X, Helgason E, Phung Q T, et al. Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation[J]. Proc Natl Acad Sci USA, 2012, 109(24): 9378-9383. [27] Manganelli F, Perfetto C, Carletta O, et al. TBK1 mutations in amyotrophic lateral sclerosis and frontotemporal dementia: mechanistic insights into impaired autophagy and proteostatic failure[J]. Cells, 2026, 15(5): 477. DOI: 10.3390/cells15050477 [28] Ryzhakov G,Randow F. SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK[J]. EMBO J, 2007, 26(13): 3180-3190. [29] Li F, Xie X, Wang Y, et al. Structural insights into the interaction and disease mechanism of neurodegenerative disease-associated optineurin and TBK1 proteins[J]. Nat Commun, 2016, 13(7):12708. DOI:10.1038/ncomms12708 [30] Larabi A, Devos J M, Ng S L, et al. Crystal structure and mechanism of activation of TANK-binding kinase 1[J]. Cell Rep, 2013, 3(3): 734-746. [31] Zhang Z,Zhang C. Regulation of cGAS-STING signalling and its diversity of cellular outcomes[J]. Nat Rev Immunol, 2025, 25(6): 425-444. [32] Hopfner K P, Hornung V. Molecular mechanisms and cellular functions of cGAS-STING signalling[J]. Nat Rev Mol Cell Biol, 2020, 21(9): 501-521. [33] van Huizen M,Gack M U. The RIG-I-like receptor family of immune proteins[J]. Mol Cell, 2025, 85(20): 3793-3806. [34] Moncrieffe M C, Suresh P, Boyle J, et al. Toll-like receptor signaling outcome is determined by the stoichio-metry of the endogenous TRIFosome[J]. Sci Adv, 2026, 12(10): eaeb9507. DOI:10.1126/sciadv.aeb9507 [35] Paul S, Biswas S R, Milner J P, et al. Adaptor-mediated trafficking of tank binding kinase 1 during diverse cellular processes[J]. Traffic, 2025, 26(1-3): e70000. DOI:10.1111/tra.70000 [36] Adriaenssens E, Nguyen T N, Sawa-Makarska J, et al. Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD[J]. Nat Struct Mol Biol, 2024, 31(11): 1717-1731. [37] Yamano K, Sawada M, Kikuchi R, et al. Optineurin provides a mitophagy contact site for TBK1 activation[J]. EMBO J, 2024, 43(5): 754-779. [38] Ujevic A, Knizkova D, Synackova A, et al. TBK1-associated adapters TANK and AZI2 protect mice against TNF-induced cell death and severe autoinflammatory diseases[J]. Nat Commun, 2024, 15(1): 10013. DOI:10.1038/s41467-024-54399-4 [39] Ogawa E, Mukai K, Saito K, et al. The binding of TBK1 to STING requires exocytic membrane traffic from the ER[J]. Biochem Biophys Res Commun, 2018, 503(1): 138-145. [40] Mukai K, Konno H, Akiba T, et al. Activation of STING requires palmitoylation at the Golgi[J]. Nat Commun, 2016, 21(7): 11932. DOI:10.1038/ncomms11932 [41] Liu S, Cai X, Wu J, et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation[J]. Science, 2015, 347(6227): aaa2630. DOI:10.1126/science.aaa2630 [42] Shang G, Zhang C, Chen Z J, et al. Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP[J]. Nature, 2019, 567(7748): 389-393. [43] Meylan E, Curran J, Hofmann K, et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus[J]. Nature, 2005, 437(7062): 1167-1172. [44] Kawai T, Takahashi K, Sato S, et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction[J]. Nat Immunol, 2005, 6(10): 981-988. [45] Hou F, Sun L, Zheng H, et al. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response[J]. Cell, 2011, 146(3): 448-461. [46] Liu S, Chen J, Cai X, et al. MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades[J]. Elife, 2013, 14(2): e00785. DOI:10.7554/eLife.00785 [47] Fang R, Jiang Q, Zhou X, et al. MAVS activates TBK1 and IKKepsilon through TRAFs in NEMO dependent and independent manner[J]. PLoS Pathog, 2017, 13(11): e1006720. DOI:10.1371/journal.ppat.1006720 [48] Dixit E, Boulant S, Zhang Y, et al. Peroxisomes are signaling platforms for antiviral innate immunity[J]. Cell, 2010, 141(4): 668-681. [49] Manik M K, Pan M, Xiao L, et al. Structural basis for TIR domain-mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM[J]. Proc Natl Acad Sci U S A, 2025, 122(2): e2418988122. DOI:10.1073/pnas.2418988122 [50] Kagan J C, Su T, Horng T, et al. TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta[J]. Nat Immunol, 2008, 9(4): 361-368. [51] Schultz T E, Mathmann C D, Dominguez Cadena L C, et al. TLR4 endocytosis and endosomal TLR4 signaling are distinct and independent outcomes of TLR4 activation[J]. EMBO Rep, 2025, 26(10): 2740-2766. [52] Kawai T, Ikegawa M, Ori D, et al. Decoding Toll-like receptors: recent insights and perspectives in innate immunity[J]. Immunity, 2024, 57(4): 649-673. [53] Sakaniwa K, Fujimura A, Shibata T, et al. TLR3 forms a laterally aligned multimeric complex along double-stranded RNA for efficient signal transduction[J]. Nat Commun, 2023, 14(1): 164. DOI:10.1038/s41467-023-35844-2 [54] Oganesyan G, Saha S K, Guo B, et al. Critical role of TRAF3 in the Toll-like receptor-dependent and-independent antiviral response[J]. Nature, 2006, 439(7073): 208-211. [55] Liu T, Zhang L, Joo D, et al. NF-kappaB signaling in inflammation[J]. Signal Transduct Target Ther, 2017, 2:17023. DOI:10.1038/sigtrans.2017.23 [56] Hacker H, Redecke V, Blagoev B, et al. Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6[J]. Nature, 2006, 439(7073): 204-207. [57] Lin Y, Yang J, Yang Q, et al. PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling[J]. Nat Commun, 2023, 14(1): 7567. DOI:10.1038/s41467-023-43419-4 [58] Song G, Liu B, Li Z, et al. E3 ubiquitin ligase RNF128 promotes innate antiviral immunity through K63-linked ubiquitination of TBK1[J]. Nat Immunol, 2016, 17(12): 1342-1351. [59] Wang C, Chen T, Zhang J, et al. The E3 ubiquitin ligase Nrdp1 ‘preferentially’ promotes TLR-mediated production of TYPE I interferon[J]. Nat Immunol, 2009, 10(7): 744-752. [60] Li S, Wang L, Berman M, et al. Mapping a dynamic innate immunity protein interaction network regulating TYPE I interferon production[J]. Immunity, 2011, 35(3): 426-440. [61] Li X, Yang M, Yu Z, et al. The tyrosine kinase Src promotes phosphorylation of the kinase TBK1 to facilitate TYPE I interferon production after viral infection[J]. Sci Signal, 2017, 10(460): 0435. DOI:10.1126/scisignal.aae0435 [62] Liu S, Chen S, Li X, et al. Lck/Hck/Fgr-mediated tyrosine phosphorylation negatively regulates TBK1 to restrain innate antiviral responses[J]. Cell Host Microbe, 2017, 21(6): 754-768. [63] Wu S, Zhang Q, Zhang F, et al. HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defence and antitumour immunity[J]. Nat Cell Biol, 2019, 21(8): 1027-1040. [64] Zhu L, Li Y, Xie X, et al. TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis[J]. Nat Cell Biol, 2019, 21(12): 1604-1614. [65] An T, Li S, Pan W, et al. DYRK2 negatively regulates TYPE I interferon induction by promoting TBK1 degradation via Ser527 phosphorylation[J]. PLoS Pathog, 2015, 11(9): e1005179. DOI:10.1371/journal.ppat.1005179 [66] Zhao Y, Liang L, Fan Y, et al. PPM1B negatively regulates antiviral response via dephosphorylating TBK1[J]. Cell Signal, 2012, 24(11): 2197-2204. [67] Zhan Z, Cao H, Xie X, et al. Phosphatase PP4 negatively regulates TYPE I IFN production and antiviral innate immunity by dephosphorylating and deactivating TBK1[J]. J Immunol, 2015, 195(8): 3849-3857. [68] Qi D, Hu L, Jiao T, et al. Phosphatase Cdc25A negatively regulates the antiviral immune response by inhibiting TBK1 activity[J]. J Virol, 2018, 92(19): e01118. DOI:10.1128/JVI.01118-18 [69] Cui J, Li Y, Zhu L, et al. NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4[J]. Nat Immunol, 2012, 13(4): 387-395. [70] Zhang M, Wang L, Zhao X, et al. TRAF-interacting protein(TRIP)negatively regulates IFN-beta production and antiviral response by promoting proteasomal degradation of TANK-binding kinase 1[J]. J Exp Med, 2012, 209(10): 1703-1711. [71] Zheng Q, Hou J, Zhou Y, et al. Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27[J]. Cell Res, 2015, 25(10): 1121-1136. [72] Lin M, Zhao Z, Yang Z, et al. USP38 inhibits Type I interferon signaling by editing TBK1 ubiquitination through NLRP4 signalosome[J]. Mol Cell, 2016, 64(2): 267-281. [73] Zhang L, Zhao X, Zhang M, et al. Ubiquitin-specific protease 2b negatively regulates IFN-beta production and antiviral activity by targeting TANK-binding kinase 1[J]. J Immunol, 2014, 193(5): 2230-2237. [74] Friedman C S, ODonnell M A, Legarda-Addison D, et al. The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response[J]. EMBO Rep, 2008, 9(9): 930-936. [75] Yu Z, Song H, Jia M, et al. USP1-UAF1 deubiquitinase complex stabilizes TBK1 and enhances antiviral responses[J]. J Exp Med, 2017, 214(12): 3553-3563. [76] Chai L, Li C, Wang X, et al. IRG1 catalyzed energy metabolite itaconic acid restrains TYPE I interferon-dependent immune responses by alkylation of TBK1[J]. Cell Rep, 2025, 44(10): 116336. DOI:10.1016/j.celrep.2025.116336 [77] Zhang X, Ling C, Xiong Z, et al. Desuccinylation of TBK1 by SIRT5 regulates inflammatory response of macrophages in sepsis[J]. Cell Rep, 2024, 43(12): 115060. DOI:10.1016/j.celrep.2024.115060 [78] Xie Y, Zhang Y, Peng W, et al. Dynamic regulation of TBK1 lactylation shapes antiviral immune responses[J]. Cell Mol Immunol, 2026, 23(3): 284-300. [79] Wang Y, Wang P, Zhang Y, et al. Decreased expression of the host long-noncoding RNA-GM facilitates viral escape by inhibiting the kinase activity TBK1 via S-glutathionylation[J]. Immunity, 2020, 53(6): 1168-1181. [80] Parvatiyar K, Barber G N,Harhaj E W. TAX1BP1 and A20 inhibit antiviral signaling by targeting TBK1-IKKi kinases[J]. J Biol Chem, 2010, 285(20): 14999-15009. [81] Gao L, Coope H, Grant S, et al. ABIN1 protein cooperates with TAX1BP1 and A20 proteins to inhibit antiviral signaling[J]. J Biol Chem, 2011, 286(42): 36592-36602. [82] Xie W, Jin S, Zhang C, et al. Selective autophagy controls the stability of TBK1 via NEDD4 to balance host defense[J]. Cell Death Differ, 2022, 29(1): 40-53. [83] Zhao X, Di Q, Yu J, et al. USP19(ubiquitin specific peptidase 19)promotes TBK1(TANK-binding kinase 1)degradation via chaperone-mediated autophagy[J]. Autophagy, 2022, 18(4): 891-908. [84] Tang J L, Yang Q, Xu C H, et al. Histone deacetylase 3 promotes innate antiviral immunity through deacetylation of TBK1[J]. Protein Cell, 2021, 12(4): 261-278. [85] Han Z, Xiong S, Zeng K, et al. Palmitoylation of TBK1 enhances the type I interferon signaling and strengthens anti-malarial immunity in mice[J]. Nat Commun, 2025, 16(1): 10109. DOI:10.1038/s41467-025-65081-8 [86] Saul V V, Niedenthal R, Pich A, et al. SUMO modification of TBK1 at the adaptor-binding C-terminal coiled-coil domain contributes to its antiviral activity[J]. Biochim Biophys Acta, 2015, 1853(1): 136-143. [87] Yan Z, Wu H, Liu H, et al. The protein arginine methyltransferase PRMT1 promotes TBK1 activation through asymmetric arginine methylation[J]. Cell Rep, 2021, 36(12): 109731. DOI:10.1016/j.celrep.2021.109731 [88] Liu Y, Yin W, Zeng X, et al. TBK1-stabilized ZNF268a recruits SETD4 to methylate TBK1 for efficient interferon signaling[J]. J Biol Chem, 2023, 299(12): 105428. DOI:10.1016/j.jbc.2023.105428 [89] Liu H, Wang S, Wang J, et al. Energy metabolism in health and diseases[J]. Signal Transduct Target Ther, 2025, 10(1): 69. DOI:10.1038/s41392-025-02141-x [90] Liu G, Zhang H, Chen S, et al. Mitochondrial calcium uniporter links acetyl-CoA metabolism and H3K27 acetylation to maintain glioblastoma stem cells[J]. Cancer Res, 2025, 85(18): 3416-3434. [91] Ghosh-Choudhary S, Liu JFinkel T. Metabolic regulation of cell fate and function[J]. Trends Cell Biol, 2020, 30(3): 201-212. [92] Chen J, Huang Z, Chen Y, et al. Lactate and lactylation in cancer[J]. Signal Transduct Target Ther, 2025, 10(1): 38. DOI:10.1038/s41392-024-02082-x [93] Zhang Q, Liu S, Zhang C S, et al. AMPK directly phosphorylates TBK1 to integrate glucose sensing into innate immunity[J]. Mol Cell, 2022, 82(23): 4519-4536. [94] Huh J Y, Reilly S M, Abu-Odeh M, et al. TANK-binding kinase 1 regulates the localization of Acyl-CoA synthetase ACSL1 to control hepatic fatty acid oxidation[J]. Cell Metab, 2020, 32(6): 1012-1027. [95] Du J, Li C, Chai L, et al. Asparagine sensing by TBK1 controls its phase separation to drive antiviral innate immune responses[J]. Mol Cell, 2026, 86(4): 722-739. [96] Hooftman A, Keller A. Ablasser A. The cGAS-STING pathway: mechanism and medical implications[J]. Cell, 2026, 189(13): 3849-3870. [97] Yum S, Li M, Fang Y, et al. TBK1 recruitment to STING activates both IRF3 and NF-kappaB that mediate immune defense against tumors and viral infections[J]. Proc Natl Acad Sci U S A, 2021, 118(14): e2100225118. DOI:10.1073/pnas.2100225118 [98] Taft J, Markson M, Legarda D, et al. Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death[J]. Cell, 2021, 184(17): 4447-4463. [99] Runde A P, Mack R, Peter B S J, et al. The role of TBK1 in cancer pathogenesis and anticancer immunity[J]. J Exp Clin Cancer Res, 2022, 41(1): 135. DOI:10.1186/s13046-022-02352-y [100] Richter B, Sliter D A, Herhaus L, et al. Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria[J]. Proc Natl Acad Sci U S A, 2016, 113(15): 4039-4044. [101] Matsumoto G, Wada K, Okuno M, et al. Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins[J]. Mol Cell, 2011, 44(2): 279-289. [102] Matsumoto G, Shimogori T, Hattori N, et al. TBK1 controls autophagosomal engulfment of polyubiquitinated mitochondria through p62/SQSTM1 phosphorylation[J]. Hum Mol Genet, 2015, 24(15): 4429-4442. [103] Prabakaran T, Bodda C, Krapp C, et al. Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1[J]. EMBO J, 2018, 37(8): e97858. DOI:10.15252/embj.201797858 [104] Tooley A S, Kazyken D, Bodur C, et al. The innate immune kinase TBK1 directly increases mTORC2 acti-vity and downstream signaling to Akt[J]. J Biol Chem, 2021, 297(2): 100942. DOI:10.1016/j.jbc.2021.100942 [105] Bodur C, Kazyken D, Huang K, et al. TBK1-mTOR signaling attenuates obesity-linked hyperglycemia and insulin resistance[J]. Diabetes, 2022, 71(11): 2297-2312. [106] Wisessaowapak C, Skorobogatko Y, Kim H, et al. A nutrient-responsive AMPK/TBK1 circuit restricts adipocyte catabolism[J]. JCI Insight, 2026, 11(9):e200168. DOI:10.1172/jci.insight.200168 [107] Ou Y H, Torres M, Ram R, et al. TBK1 directly engages Akt/PKB survival signaling to support oncogenic transformation[J]. Mol Cell, 2011, 41(4): 458-470. [108] 邓豪, 夏志, 尚画雨. TANK结合激酶1在PINK1/Parkin依赖性和非依赖性线粒体自噬中的作用研究进展[J]. 生理学报, 2024, 76(1): 161-172. Deng Hao, Xia Zhi, Shang Huayu. Research progress on the role of TANK-binding kinase 1 in PINK1/Parkin-dependent and-independent mitophagy[J]. Acta Physiologica Sinica, 2024, 76(1): 161-172. [109] Tang S, Geng Y,Lin Q. The role of mitophagy in metabolic diseases and its exercise intervention[J]. Front Physiol, 2024, 15: 1339128. DOI:10.3389/fphys.2024.1339128 [110] West A P, Khoury-Hanold W, Staron M, et al. Mitochondrial DNA stress primes the antiviral innate immune response[J]. Nature, 2015, 520(7548): 553-557. [111] Nakahira K, Haspel J A, Rathinam V A, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome[J]. Nat Immunol, 2011, 12(3): 222-230. [112] Garza-Lombo C, Pappa A, Panayiotidis M I, et al. Redox homeostasis, oxidative stress and mitophagy[J]. Mitochondrion, 2020, 51: 105-117. DOI:10.1016/j.mito.2020.01.002 [113] Xu D, Jin T, Zhu H, et al. TBK1 Suppresses RIPK1-driven apoptosis and inflammation during development and in aging[J]. Cell, 2018, 174(6): 1477-1491. [114] Zhang T, Xu D, Trefts E, et al. Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1[J]. Science, 2023, 380(6652): 1372-1380. [115] McWhirter S M, Fitzgerald K A, Rosains J, et al. IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts[J]. Proc Natl Acad Sci U S A, 2004, 101(1): 233-238. [116] Kilic S S, Zhao S, Liu Z, et al. Recurrent severe viral infection in a child with inherited complete TBK1 deficiency[J]. J Hum Immun, 2026, 2(1): e20250058. DOI:10.70962/jhi.20250058 [117] Akalu Y, Taft J, Berger T, et al. Human TBK1 deficiency: an expanded spectrum from autoinflammation to viral encephalitis[J]. J Hum Immun, 2026, 2(2): e20250245. DOI:10.70962/jhi.20250245 [118] Herman M, Ciancanelli M, Ou Y H, et al. Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood[J]. J Exp Med, 2012, 209(9): 1567-1582. [119] Leekha A, Saeedi A, Kumar M, et al. An intranasal nanoparticle STING agonist protects against respiratory viruses in animal models[J]. Nat Commun, 2024, 15(1): 6053. DOI:10.1038/s41467-024-50234-y [120] Li M, Ferretti M, Ying B, et al. Pharmacological activation of STING blocks SARS-CoV-2 infection[J]. Sci Immunol, 2021, 6(59): eabi9007. DOI:10.1126/sciimmunol.abi9007 [121] 王娅, 吴硕,李玉环. 干扰素基因刺激因子激动剂的研究进展[J]. 中国药理学通报, 2024, 40(4): 611-618. Wang Ya, Wu Shuo, Li Yuhuan. Research progress of STING agonists[J]. Chin Pharmacol Bull, 2024, 40(4): 611-618. [122] Ullah T R, Johansen M D, Balka K R, et al. Pharmacological inhibition of TBK1/IKKepsilon blunts immunopathology in a murine model of SARS-CoV-2 infection[J]. Nat Commun, 2023, 14(1): 5666. DOI:10.1038/s41467-023-41381-9 [123] Zhang M, Zou Y, Zhou X, et al. Inhibitory targeting cGAS-STING-TBK1 axis: emerging strategies for autoimmune diseases therapy[J]. Front Immunol, 2022, 13: 954129. DOI:10.3389/fimmu.2022.954129 [124] Xiao N, Wei J, Xu S, et al. cGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant mouse model[J]. J Autoimmun, 2019, 100:84-94. DOI:10.1016/j.jaut.2019.03.001 [125] Gray E E, Treuting P M, Woodward J J, et al. Cutting edge: cGAS is required for lethal autoimmune disease in the Trex1-deficient mouse model of aicardi-goutieres syndrome[J]. J Immunol, 2015, 195(5): 1939-1943. [126] Du H, Cui D, Hu S, et al. The induction of TYPE I interferonopathy in Trex1-P212fs mice is mediated by activation of the cGAS-STING pathway[J]. Int J Biol Macromol, 2025, 310(Pt 2): 143414. DOI:10.1016/j.ijbiomac.2025.143414 [127] Cruz V H, Arner E N, Wynne K W, et al. Loss of Tbk1 kinase activity protects mice from diet-induced metabolic dysfunction[J]. Mol Metab, 2018, 16:139-149. DOI:10.1016/j.molmet.2018.06.007 [128] Gao T, Liu T, Ko C J, et al. Myeloid cell TBK1 restricts inflammatory responses[J]. Proc Natl Acad Sci U S A, 2022, 119(4):e2107742119. DOI:10.1073/pnas.2107742119 [129] Gao C Q, Chu Z Z, Zhang D, et al. Serine/threonine kinase TBK1 promotes cholangiocarcinoma progression via direct regulation of beta-catenin[J]. Oncogene, 2023, 42(18): 1492-1507. [130] Cruz V H, Arner E N, Du W, et al. Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer[J]. JCI Insight, 2019, 5(9): e126117. DOI:10.1172/jci.insight.126117 [131] Liao C, Hu L, Jia L, et al. BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma[J]. Nat Commun, 2025, 16(1): 1543. DOI:10.1038/s41467-025-56955-y [132] Shin J, Lim J, Han D, et al. TBK1 inhibitor amle-xanox exerts anti-cancer effects against endometrial cancer by regulating AKT/NF-kappaB signaling[J]. Int J Biol Sci, 2025, 21(1): 143-159. [133] Carr M, Mamand S, Chapman K L, et al. IKKepsilon and TBK1 in diffuse large B-cell lymphoma: a possible mechanism of action of an IKKepsilon/TBK1 inhibitor to repress NF-kappaB and IL-10 signalling[J]. J Cell Mol Med, 2020, 24(19): 11573-11582. [134] Brown M C, Mosaheb M M, Mohme M, et al. Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling[J]. Nat Commun, 2021, 12(1): 1858. DOI:10.1038/s41467-021-22088-1 [135] Korac J, Schaeffer V, Kovacevic I, et al. Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates[J]. J Cell Sci, 2013, 126(Pt 2): 580-592. [136] Ahmad L, Zhang S Y, Casanova J L, et al. Human TBK1: a gatekeeper of neuroinflammation[J]. Trends Mol Med, 2016, 22(6): 511-527. [137] Lenoel I, Ribon M, Lorenc F, et al. ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits in mice[J]. Nat Commun, 2025, 16(1): 7951. DOI:10.1038/s41467-025-63211-w [138] Mifflin L, Ofengeim D.Yuan J. Receptor-interacting protein kinase 1(RIPK1)as a therapeutic target[J]. Nat Rev Drug Discov, 2020, 19(8): 553-571. [139] Clucas J,Meier P. Roles of RIPK1 as a stress sentinel coordinating cell survival and immunogenic cell death[J]. Nat Rev Mol Cell Biol, 2023, 24(11): 835-852. [140] Abreha M H, Ojelade S, Dammer E B, et al. TBK1 interacts with tau and enhances neurodegeneration in tauopathy[J]. J Biol Chem, 2021, 296:100760. DOI:10.1016/j.jbc.2021.100760 [141] Zhao B, Du F, Xu P, et al. A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1[J]. Nature, 2019, 569(7758): 718-722. [142] Thomson D W, Poeckel D, Zinn N, et al. Discovery of GSK8612, a highly selective and potent TBK1 inhibitor[J]. ACS Med Chem Lett, 2019, 10(5): 780-785. [143] 常玉, 丁克. TANK结合激酶1小分子抑制剂的研究进展[J]. 药学进展, 2019, 43(7): 504-516. Chang Yu, Ding Ke. Recent advances in research on small-molecule TBK1 inhibitors[J]. Progress in Pharmaceutical Sciences, 2019, 43(7): 504-516. [144] Crew A P, Raina K, Dong H, et al. Identification and characterization of von hippel-lindau-recruiting proteolysis targeting chimeras(PROTACs)of TANK-binding kinase 1[J]. J Med Chem, 2018, 61(2): 583-598. [145] Clark K, Plater L, Peggie M, et al. Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation[J]. J Biol Chem, 2009, 284(21): 14136-14146. [146] Clark K, Peggie M, Plater L, et al. Novel cross-talk within the IKK family controls innate immunity[J]. Biochem J, 2011, 434(1): 93-104. [147] 黄炜祺, 江高峰, 周咏明. IKKε和TBK1通路及其抑制剂在肿瘤中的作用[J]. 中国肿瘤生物治疗杂志, 2020, 27(2): 204-208. Huang Weiqi, Jiang Gaofeng, Zhou Yongming. IKKε and TBK1 pathways and their inhibitors in tumor[J]. Chinese Journal of Cancer Biotherapy, 2020, 27(2):204-208. [148] Sun L, Wu J, Du F, et al. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway[J]. Science, 2013, 339(6121): 786-791. [149] Xiao Y, Zou Q, Xie X, et al. The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity[J]. J Exp Med, 2017, 214(5): 1493-1507. [150] Lafont E, Draber P, Rieser E, et al. TBK1 and IKKepsilon prevent TNF-induced cell death by RIPK1 phosphorylation[J]. Nat Cell Biol, 2018, 20(12): 1389-1399. [151] Eren R O, Kaya G G, Schwarzer R, et al. IKKepsilon and TBK1 prevent RIPK1 dependent and independent inflammation[J]. Nat Commun, 2024, 15(1): 130. DOI:10.1038/s41467-023-44372-y [152] Almeida M S, Bezbradica J S. Coban C. TANK-binding kinase 1(TBK1): unexpected cell type-specific immune regulation beyond antiviral type I interferon signaling[J]. Curr Opin Virol, 2026, 76:101545. DOI:10.1016/j.coviro.2026.101545 |
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