id: Q9UHD2 gene_symbol: TBK1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: 'TBK1 (TANK-binding kinase 1) is a cytoplasmic non-canonical IKB kinase (IKK)-related serine/threonine protein kinase. Its domain architecture comprises an N-terminal protein kinase domain, a ubiquitin-like domain (ULD), a scaffold/dimerization domain, and a C-terminal coiled-coil region that mediates homodimerization; the active kinase is generated by trans-autophosphorylation at Ser172. TBK1 is a master kinase of innate antiviral immunity: downstream of cytoplasmic nucleic-acid sensors (RIG-I/MDA5 via MAVS; cGAS via STING1) and endosomal Toll-like receptors (TLR3/TLR4 via TRIF/TICAM1), TBK1 phosphorylates these adaptor proteins on their pLxIS motif to recruit and then phosphorylate the transcription factors IRF3 and IRF7, driving their dimerization, nuclear translocation, and induction of type I interferons (IFN-alpha/IFN-beta) and other antiviral/pro-inflammatory genes. It is the kinase effector of the cGAS-STING DNA-sensing pathway and was originally identified as an NF-kappaB-activating kinase (binding the adaptor TANK), phosphorylating RELA/NFKBIA/IKBKB under particular conditions. TBK1 is also a central kinase of selective autophagy: it phosphorylates the autophagy cargo receptors OPTN/optineurin (Ser177), SQSTM1/p62, NDP52/CALCOCO2 and TAX1BP1 to enhance their ubiquitin- and LC3-binding and drive mitophagy and antibacterial xenophagy, and it phosphorylates SMCR8 (in the C9orf72-SMCR8 complex) and the ATG8 proteins MAP1LC3C and GABARAPL2 to promote autophagosome maturation. TBK1 assembles into kinase complexes with scaffolding adaptors AZI2/NAP1, TANK and TBKBP1/SINTBAD. Additional context-dependent roles include bidirectional regulation of mTORC1/mTORC2 signaling, AKT1 activation, and immune cell differentiation. TBK1 activity is antagonized by numerous viral proteins, and human mutations cause familial ALS/frontotemporal dementia (haploinsufficiency), normal-tension/primary open-angle glaucoma, herpes-simplex encephalopathy, and autoinflammatory disease.' existing_annotations: - term: id: GO:0005737 label: cytoplasm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: 'Cytoplasm: the core compartment where TBK1 assembles into signaling complexes and phosphorylates its substrates.' action: ACCEPT reason: Core cytoplasmic localization, experimentally supported. supported_by: &id003 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: &id002 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents - term: id: GO:0002218 label: activation of innate immune response evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: 'Activation of innate immune response: core process; TBK1 activation is a central node in innate antiviral signaling.' action: ACCEPT reason: Core biological process directly supported by experimental evidence. supported_by: &id001 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 - term: id: GO:0032481 label: positive regulation of type I interferon production evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: 'Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.' action: ACCEPT reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation. supported_by: &id005 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 - term: id: GO:0002218 label: activation of innate immune response evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: 'Activation of innate immune response: core process; TBK1 activation is a central node in innate antiviral signaling.' action: ACCEPT reason: Core biological process directly supported by experimental evidence. supported_by: *id001 - term: id: GO:0004672 label: protein kinase activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: &id018 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: ATP binding by the kinase domain, part of the catalytic mechanism of TBK1. action: ACCEPT reason: Correct and integral to the core protein kinase activity. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: 'Cytoplasm: the core compartment where TBK1 assembles into signaling complexes and phosphorylates its substrates.' action: ACCEPT reason: Core cytoplasmic localization, experimentally supported. supported_by: *id003 - term: id: GO:0006952 label: defense response evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: 'Defense response: a generic parent of TBK1''s specific antiviral/innate-immune role.' action: KEEP_AS_NON_CORE reason: Correct but generic; the specific antiviral-innate-immune-response and type-I-IFN-production terms capture the core function more precisely. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 - term: id: GO:0016239 label: positive regulation of macroautophagy evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: 'Positive regulation of macroautophagy: core process; TBK1 phosphorylates autophagy receptors (OPTN Ser177) and SMCR8 to promote selective autophagy and autophagosome maturation.' action: ACCEPT reason: Core biological process directly demonstrated (OPTN, SMCR8, ATG8 phosphorylation). supported_by: &id015 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy - term: id: GO:0032008 label: positive regulation of TOR signaling evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: 'Positive regulation of TOR signaling (IEA): generic mTOR-pathway parent; secondary/pleiotropic.' action: KEEP_AS_NON_CORE reason: Generic and context-dependent; non-core. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: activates mTORC1 in response to growth factors by catalyzing phosphorylation of MTOR - term: id: GO:0032728 label: positive regulation of interferon-beta production evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: 'Positive regulation of interferon-beta production: a specific, core output of TBK1-mediated IRF3 activation.' action: ACCEPT reason: Core biological process; TBK1 induces IFN-beta via IRF3. supported_by: &id013 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB - term: id: GO:0043123 label: positive regulation of canonical NF-kappaB signal transduction evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: 'Positive regulation of canonical NF-kappaB signal transduction: the founding role of TBK1 (TANK-binding kinase) as an IKK-related NF-kappaB-activating kinase.' action: ACCEPT reason: Well-supported biological process; TBK1 was identified as an NF-kappaB-activating IKK-related kinase and phosphorylates RELA/NFKBIA/IKBKB under particular conditions. supported_by: &id017 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus - term: id: GO:0051707 label: response to other organism evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: 'Response to other organism: a generic parent of TBK1''s specific antiviral/innate-immune role.' action: KEEP_AS_NON_CORE reason: Correct but generic; the specific antiviral-innate-immune-response and type-I-IFN-production terms capture the core function more precisely. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: IEA original_reference_id: GO_REF:0000116 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: &id006 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:14743216 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: &id004 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:15841462 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16306936 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17568778 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17599067 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18307994 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18583960 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18724357 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19153231 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19380580 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19416887 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19433799 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20098747 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20562859 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21903422 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21931555 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21988832 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22000020 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22939624 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23096996 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23414517 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23542348 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24509444 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24622840 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24643253 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24696485 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24807708 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25803835 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27086836 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27094905 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27135603 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:29251827 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:30561431 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32353859 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32707033 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32979938 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33060197 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33372174 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33707416 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:34084167 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:34166398 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:34524948 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:37219487 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0003676 label: nucleic acid binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Nucleic acid binding, transferred electronically from the mouse ortholog (Ensembl Compara). TBK1 is a protein serine/threonine kinase; there is no experimental support for it being a sequence-nonspecific nucleic-acid-binding protein. action: MARK_AS_OVER_ANNOTATED reason: Electronic ortholog transfer with no experimental basis for TBK1; biologically implausible as a molecular function for this protein kinase. Flagged as over-annotation (electronic, not experimental). supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents - term: id: GO:0010629 label: negative regulation of gene expression evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Negative regulation of gene expression, transferred electronically from the mouse ortholog. The documented role of TBK1 is to positively drive antiviral/inflammatory gene expression (IFNs) via IRF3/IRF7; a generic negative-regulation term mischaracterizes the core function. action: MARK_AS_OVER_ANNOTATED reason: Overly generic electronic ortholog transfer that does not reflect the documented positive, IRF-driven transcriptional role; flagged as over-annotation. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB - term: id: GO:0019903 label: protein phosphatase binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Protein phosphatase binding, inferred by orthology (IEA/ISS). Relates to regulation of TBK1 phosphorylation status; not a core function. action: KEEP_AS_NON_CORE reason: Orthology-based interaction property; non-core. supported_by: &id014 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents - term: id: GO:0042802 label: identical protein binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Identical protein binding (homodimerization), inferred electronically from the mouse ortholog. TBK1 does homodimerize via its C-terminal coiled-coil, but the term is uninformative. action: KEEP_AS_NON_CORE reason: Real homodimerization but the term is uninformative; the coiled-coil-mediated dimerization is better described at the structural level. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: and a C-terminal coiled-coil region mediating homodimerization. - term: id: GO:0060340 label: positive regulation of type I interferon-mediated signaling pathway evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Positive regulation of type I interferon-mediated signaling pathway (IEA ortholog). Same caveat as GO:0060337 - TBK1's documented role is in IFN induction rather than downstream IFN-receptor signaling. action: KEEP_AS_NON_CORE reason: Orthology-based; imprecise relative to TBK1's induction role. Non-core. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 - term: id: GO:1904417 label: positive regulation of xenophagy evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'Positive regulation of xenophagy: TBK1 phosphorylates OPTN on Ser177 to drive selective autophagy of cytosolic bacteria (e.g. Salmonella).' action: ACCEPT reason: Core biological process directly demonstrated for antibacterial (xeno)phagy. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy - term: id: GO:1904515 label: positive regulation of TORC2 signaling evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'Positive regulation of TORC2 signaling (ISS/IEA, by orthology): TBK1 promotes mTORC2-dependent AKT1 activation. Secondary/pleiotropic role.' action: KEEP_AS_NON_CORE reason: Orthology-based, secondary role; non-core relative to innate immunity/autophagy. supported_by: &id010 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Acts as a positive regulator of the mTORC2 complex by mediating phosphorylation of MTOR - term: id: GO:0016236 label: macroautophagy evidence_type: TAS original_reference_id: Reactome:R-HSA-5205685 qualifier: involved_in review: summary: Macroautophagy (Reactome PINK1-PRKN mitophagy TAS). A generic parent of TBK1's specific positive-regulatory autophagy role. action: KEEP_AS_NON_CORE reason: Correct but generic; the positive-regulation-of-macroautophagy/xenophagy terms capture the core function. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy - term: id: GO:0032481 label: positive regulation of type I interferon production evidence_type: TAS original_reference_id: Reactome:R-HSA-1834941 qualifier: involved_in review: summary: 'Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.' action: ACCEPT reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation. supported_by: *id005 - term: id: GO:0032481 label: positive regulation of type I interferon production evidence_type: TAS original_reference_id: Reactome:R-HSA-3270619 qualifier: involved_in review: summary: 'Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.' action: ACCEPT reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation. supported_by: *id005 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: EXP original_reference_id: PMID:27035970 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: TAS original_reference_id: Reactome:R-HSA-2396007 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: TAS original_reference_id: Reactome:R-HSA-3249371 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: TAS original_reference_id: Reactome:R-HSA-933525 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0005654 label: nucleoplasm evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: 'Nucleoplasm (IDA, immunofluorescence/HPA): a minor pool. TBK1 is predominantly cytoplasmic and acts there.' action: KEEP_AS_NON_CORE reason: Minor/secondary localization; the dominant functional pool is cytoplasmic. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:15485837 qualifier: located_in review: summary: 'Cytoplasm: the core compartment where TBK1 assembles into signaling complexes and phosphorylates its substrates.' action: ACCEPT reason: Core cytoplasmic localization, experimentally supported. supported_by: *id003 - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:32298923 qualifier: located_in review: summary: 'Cytoplasm: the core compartment where TBK1 assembles into signaling complexes and phosphorylates its substrates.' action: ACCEPT reason: Core cytoplasmic localization, experimentally supported. supported_by: *id003 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:10783893 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id006 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:14703513 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id006 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:15367631 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id006 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:18583960 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id006 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:21138416 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id006 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:21270402 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id006 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:21464307 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id006 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:21617041 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id006 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:25636800 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id006 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:29150432 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id006 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:31530866 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id006 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:31709703 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id006 - term: id: GO:0051607 label: defense response to virus evidence_type: NAS original_reference_id: PMID:17142768 qualifier: involved_in review: summary: 'Defense response to virus: a core, well-supported biological process; TBK1 is essential for antiviral defense via IRF3/type I IFN.' action: ACCEPT reason: Core biological process strongly supported across the literature. supported_by: &id007 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 - term: id: GO:0051607 label: defense response to virus evidence_type: NAS original_reference_id: PMID:21931631 qualifier: involved_in review: summary: 'Defense response to virus: a core, well-supported biological process; TBK1 is essential for antiviral defense via IRF3/type I IFN.' action: ACCEPT reason: Core biological process strongly supported across the literature. supported_by: *id007 - term: id: GO:0051607 label: defense response to virus evidence_type: NAS original_reference_id: PMID:24622840 qualifier: involved_in review: summary: 'Defense response to virus: a core, well-supported biological process; TBK1 is essential for antiviral defense via IRF3/type I IFN.' action: ACCEPT reason: Core biological process strongly supported across the literature. supported_by: *id007 - term: id: GO:0060337 label: type I interferon-mediated signaling pathway evidence_type: NAS original_reference_id: PMID:17142768 qualifier: involved_in review: summary: Type I interferon-mediated signaling pathway. TBK1 acts in IFN *induction* (driving IRF3/IFN gene expression) rather than in downstream IFN-receptor (JAK/STAT) signaling that this term most precisely denotes. action: KEEP_AS_NON_CORE reason: 'Correct pathway context but imprecise: TBK1''s role is upstream IFN induction; the positive-regulation-of-type-I-IFN-production terms capture the core function.' supported_by: &id008 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 - term: id: GO:0060337 label: type I interferon-mediated signaling pathway evidence_type: NAS original_reference_id: PMID:21931631 qualifier: involved_in review: summary: Type I interferon-mediated signaling pathway. TBK1 acts in IFN *induction* (driving IRF3/IFN gene expression) rather than in downstream IFN-receptor (JAK/STAT) signaling that this term most precisely denotes. action: KEEP_AS_NON_CORE reason: 'Correct pathway context but imprecise: TBK1''s role is upstream IFN induction; the positive-regulation-of-type-I-IFN-production terms capture the core function.' supported_by: *id008 - term: id: GO:1902554 label: serine/threonine protein kinase complex evidence_type: NAS original_reference_id: PMID:17142768 qualifier: part_of review: summary: 'Serine/threonine protein kinase complex: TBK1 functions within kinase complexes (e.g. the TBK1-IKKepsilon-NAP1/TANK/SINTBAD complexes).' action: ACCEPT reason: Core cellular component; TBK1 acts as part of ser/thr kinase complexes with its adaptors. supported_by: &id009 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes - term: id: GO:1902554 label: serine/threonine protein kinase complex evidence_type: NAS original_reference_id: PMID:21931631 qualifier: part_of review: summary: 'Serine/threonine protein kinase complex: TBK1 functions within kinase complexes (e.g. the TBK1-IKKepsilon-NAP1/TANK/SINTBAD complexes).' action: ACCEPT reason: Core cellular component; TBK1 acts as part of ser/thr kinase complexes with its adaptors. supported_by: *id009 - term: id: GO:1902554 label: serine/threonine protein kinase complex evidence_type: NAS original_reference_id: PMID:24622840 qualifier: part_of review: summary: 'Serine/threonine protein kinase complex: TBK1 functions within kinase complexes (e.g. the TBK1-IKKepsilon-NAP1/TANK/SINTBAD complexes).' action: ACCEPT reason: Core cellular component; TBK1 acts as part of ser/thr kinase complexes with its adaptors. supported_by: *id009 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18818105 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0002753 label: cytoplasmic pattern recognition receptor signaling pathway evidence_type: IDA original_reference_id: PMID:29441066 qualifier: involved_in review: summary: 'Cytoplasmic pattern recognition receptor signaling pathway: TBK1 functions downstream of cytoplasmic RNA/DNA sensors (RIG-I/MDA5-MAVS, cGAS-STING).' action: ACCEPT reason: Core biological process; TBK1 transduces cytoplasmic PRR signals to IRF3. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:14703513 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:14703513 qualifier: is_active_in review: summary: 'Cytoplasm: the core compartment where TBK1 assembles into signaling complexes and phosphorylates its substrates.' action: ACCEPT reason: Core cytoplasmic localization, experimentally supported. supported_by: *id003 - term: id: GO:0061629 label: RNA polymerase II-specific DNA-binding transcription factor binding evidence_type: IPI original_reference_id: PMID:22412986 qualifier: enables review: summary: RNA polymerase II transcription factor binding (IRF5), recording TBK1 binding to its IRF substrate. The informative function is the kinase activity that phosphorylates IRFs. action: KEEP_AS_NON_CORE reason: Records an IRF (substrate) interaction; subsumed by the core kinase activity and IFN-production annotations. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: IDA original_reference_id: PMID:22412986 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id006 - term: id: GO:0140896 label: cGAS/STING signaling pathway evidence_type: TAS original_reference_id: PMID:37403426 qualifier: involved_in review: summary: 'cGAS/STING signaling pathway: TBK1 is the kinase recruited by activated STING1 that phosphorylates STING1 and IRF3 in the cytosolic DNA-sensing pathway.' action: ACCEPT reason: Core biological process; TBK1 is an essential kinase of the cGAS-STING axis. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:1904515 label: positive regulation of TORC2 signaling evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: 'Positive regulation of TORC2 signaling (ISS/IEA, by orthology): TBK1 promotes mTORC2-dependent AKT1 activation. Secondary/pleiotropic role.' action: KEEP_AS_NON_CORE reason: Orthology-based, secondary role; non-core relative to innate immunity/autophagy. supported_by: *id010 - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:21813773 qualifier: is_active_in review: summary: 'Cytosol: the core subcellular location of TBK1 signaling activity.' action: ACCEPT reason: Core cytosolic localization consistent with experimental cytoplasmic localization. supported_by: &id011 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0032481 label: positive regulation of type I interferon production evidence_type: IDA original_reference_id: PMID:25636800 qualifier: involved_in review: summary: 'Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.' action: ACCEPT reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation. supported_by: *id005 - term: id: GO:0061470 label: T follicular helper cell differentiation evidence_type: IDA original_reference_id: PMID:27135603 qualifier: involved_in review: summary: 'T follicular helper cell differentiation: TBK1 participates with ICOS in TFH/TFR cell differentiation. A specialized, developmental/immunological role.' action: KEEP_AS_NON_CORE reason: Specialized pleiotropic role; non-core relative to the kinase's central innate-immune/autophagy functions. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: participates in the differentiation of T follicular regulatory cells together with the receptor ICOS - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32209697 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0140374 label: antiviral innate immune response evidence_type: IDA original_reference_id: PMID:14703513 qualifier: involved_in review: summary: 'Antiviral innate immune response: a core biological process for TBK1, which phosphorylates IRF3 (e.g. Ser-386) and the adaptors STING1/MAVS/TRIF to drive antiviral gene expression.' action: ACCEPT reason: Core biological process directly demonstrated; TBK1 is a master kinase of antiviral innate immunity. supported_by: &id012 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: TAS original_reference_id: PMID:37403426 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: PMID:37403426 qualifier: is_active_in review: summary: 'Cytosol: the core subcellular location of TBK1 signaling activity.' action: ACCEPT reason: Core cytosolic localization consistent with experimental cytoplasmic localization. supported_by: *id011 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:22394562 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0032481 label: positive regulation of type I interferon production evidence_type: IDA original_reference_id: PMID:22394562 qualifier: involved_in review: summary: 'Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.' action: ACCEPT reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation. supported_by: *id005 - term: id: GO:0140374 label: antiviral innate immune response evidence_type: IDA original_reference_id: PMID:22394562 qualifier: involved_in review: summary: 'Antiviral innate immune response: a core biological process for TBK1, which phosphorylates IRF3 (e.g. Ser-386) and the adaptors STING1/MAVS/TRIF to drive antiviral gene expression.' action: ACCEPT reason: Core biological process directly demonstrated; TBK1 is a master kinase of antiviral innate immunity. supported_by: *id012 - term: id: GO:0002218 label: activation of innate immune response evidence_type: IDA original_reference_id: PMID:25636800 qualifier: involved_in review: summary: 'Activation of innate immune response: core process; TBK1 activation is a central node in innate antiviral signaling.' action: ACCEPT reason: Core biological process directly supported by experimental evidence. supported_by: *id001 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:29150432 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:31530866 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:1904262 label: negative regulation of TORC1 signaling evidence_type: IDA original_reference_id: PMID:31530866 qualifier: involved_in review: summary: 'Negative regulation of TORC1 signaling: TBK1 limits mTORC1 by phosphorylating RPTOR (Ser877). A context-dependent, secondary role opposite to its TORC1-activating role.' action: KEEP_AS_NON_CORE reason: Real but context-dependent/pleiotropic; non-core. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: it limits the mTORC1 complex by promoting phosphorylation of RPTOR - term: id: GO:1904263 label: positive regulation of TORC1 signaling evidence_type: IDA original_reference_id: PMID:29150432 qualifier: involved_in review: summary: 'Positive regulation of TORC1 signaling: TBK1 activates mTORC1 in response to growth factors (MTOR phosphorylation). A context-dependent, secondary role.' action: KEEP_AS_NON_CORE reason: Real but context-dependent and pleiotropic; opposite TORC1 effects are reported depending on stimulus. Non-core relative to innate immunity/autophagy. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: activates mTORC1 in response to growth factors by catalyzing phosphorylation of MTOR - term: id: GO:0034142 label: toll-like receptor 4 signaling pathway evidence_type: IDA original_reference_id: PMID:28747347 qualifier: involved_in review: summary: 'Toll-like receptor 4 signaling pathway: TBK1 acts downstream of TLR4 (via TRIF) to activate IRF3. An upstream-pathway context for its IFN-induction role.' action: KEEP_AS_NON_CORE reason: Correct pathway context; the antiviral-innate-immune and type-I-IFN terms are the core capture. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors - term: id: GO:0032481 label: positive regulation of type I interferon production evidence_type: IDA original_reference_id: PMID:14703513 qualifier: involved_in review: summary: 'Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.' action: ACCEPT reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation. supported_by: *id005 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:22921120 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0010508 label: positive regulation of autophagy evidence_type: IDA original_reference_id: PMID:28871090 qualifier: involved_in review: summary: 'Positive regulation of autophagy: core process driven by TBK1 phosphorylation of autophagy machinery and receptors.' action: ACCEPT reason: Core biological process directly demonstrated. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:29441066 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0032728 label: positive regulation of interferon-beta production evidence_type: IDA original_reference_id: PMID:31390091 qualifier: acts_upstream_of_or_within review: summary: 'Positive regulation of interferon-beta production: a specific, core output of TBK1-mediated IRF3 activation.' action: ACCEPT reason: Core biological process; TBK1 induces IFN-beta via IRF3. supported_by: *id013 - term: id: GO:0032481 label: positive regulation of type I interferon production evidence_type: IDA original_reference_id: PMID:29441066 qualifier: involved_in review: summary: 'Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.' action: ACCEPT reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation. supported_by: *id005 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:31709703 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9823904 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9828200 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20628368 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:30354798 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:31662325 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:29251827 qualifier: located_in review: summary: 'Cytoplasm: the core compartment where TBK1 assembles into signaling complexes and phosphorylates its substrates.' action: ACCEPT reason: Core cytoplasmic localization, experimentally supported. supported_by: *id003 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28011935 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:25636800 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0018105 label: peptidyl-serine phosphorylation evidence_type: IDA original_reference_id: PMID:25636800 qualifier: involved_in review: summary: 'Peptidyl-serine phosphorylation: a generic process description of TBK1''s kinase activity.' action: KEEP_AS_NON_CORE reason: Correct but generic; the protein serine/threonine kinase activity (MF) and the specific signaling-pathway terms are more informative. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents - term: id: GO:0018107 label: peptidyl-threonine phosphorylation evidence_type: IDA original_reference_id: PMID:25636800 qualifier: involved_in review: summary: 'Peptidyl-threonine phosphorylation: a generic process description of TBK1''s kinase activity.' action: KEEP_AS_NON_CORE reason: Correct but generic; the protein serine/threonine kinase activity (MF) and the specific signaling-pathway terms are more informative. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents - term: id: GO:0032479 label: regulation of type I interferon production evidence_type: IDA original_reference_id: PMID:25636800 qualifier: involved_in review: summary: 'Regulation of type I interferon production: core regulatory role of TBK1 via adaptor and IRF3 phosphorylation.' action: ACCEPT reason: Core biological process; consistent with the positive-regulation-of-type-I-IFN annotations. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 - term: id: GO:0045087 label: innate immune response evidence_type: IDA original_reference_id: PMID:25636800 qualifier: involved_in review: summary: 'Innate immune response: core biological process for TBK1.' action: ACCEPT reason: Core biological process; TBK1 is central to innate immune signaling. supported_by: &id016 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 - term: id: GO:0019903 label: protein phosphatase binding evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables review: summary: Protein phosphatase binding, inferred by orthology (IEA/ISS). Relates to regulation of TBK1 phosphorylation status; not a core function. action: KEEP_AS_NON_CORE reason: Orthology-based interaction property; non-core. supported_by: *id014 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9008684 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:27103069 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27103069 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0006468 label: protein phosphorylation evidence_type: IDA original_reference_id: PMID:27103069 qualifier: involved_in review: summary: 'Protein phosphorylation: a generic process description of TBK1''s kinase activity.' action: KEEP_AS_NON_CORE reason: Correct but generic; the protein serine/threonine kinase activity (MF) and the specific signaling-pathway terms are more informative. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24560620 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0016239 label: positive regulation of macroautophagy evidence_type: IDA original_reference_id: PMID:27103069 qualifier: involved_in review: summary: 'Positive regulation of macroautophagy: core process; TBK1 phosphorylates autophagy receptors (OPTN Ser177) and SMCR8 to promote selective autophagy and autophagosome maturation.' action: ACCEPT reason: Core biological process directly demonstrated (OPTN, SMCR8, ATG8 phosphorylation). supported_by: *id015 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25736436 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:25803835 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24056301 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-3249386 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8948709 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-1606327 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-166245 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-166271 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-2396002 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-2396007 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-3249371 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-3249390 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-3249392 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8948703 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9013978 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9013979 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-918229 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-918232 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-933525 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-933538 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9679819 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9705320 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9705323 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9817397 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9817411 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9823906 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9824892 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9824894 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9824897 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9828205 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9840807 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21813773 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:21813773 qualifier: located_in review: summary: 'Cytoplasm: the core compartment where TBK1 assembles into signaling complexes and phosphorylates its substrates.' action: ACCEPT reason: Core cytoplasmic localization, experimentally supported. supported_by: *id003 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18636086 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: TAS original_reference_id: PMID:21042276 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id002 - term: id: GO:0006954 label: inflammatory response evidence_type: TAS original_reference_id: PMID:21042276 qualifier: involved_in review: summary: Inflammatory response (review TAS). A broad downstream consequence of TBK1 signaling. action: KEEP_AS_NON_CORE reason: Broad/secondary process; the specific IFN and NF-kappaB signaling terms are more informative. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents - term: id: GO:0007249 label: canonical NF-kappaB signal transduction evidence_type: TAS original_reference_id: PMID:21042276 qualifier: involved_in review: summary: Canonical NF-kappaB signal transduction (TAS). Records TBK1's NF-kappaB-pathway involvement; the positive-regulation term is the more informative capture. action: KEEP_AS_NON_CORE reason: Correct pathway context; subsumed by the positive-regulation-of-canonical-NF-kappaB annotation. supported_by: &id019 - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA - term: id: GO:0009615 label: response to virus evidence_type: TAS original_reference_id: PMID:21042276 qualifier: involved_in review: summary: 'Response to virus: a generic parent of TBK1''s specific antiviral/innate-immune role.' action: KEEP_AS_NON_CORE reason: Correct but generic; the specific antiviral-innate-immune-response and type-I-IFN-production terms capture the core function more precisely. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 - term: id: GO:0032481 label: positive regulation of type I interferon production evidence_type: TAS original_reference_id: PMID:21042276 qualifier: involved_in review: summary: 'Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.' action: ACCEPT reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation. supported_by: *id005 - term: id: GO:0045087 label: innate immune response evidence_type: TAS original_reference_id: PMID:21042276 qualifier: involved_in review: summary: 'Innate immune response: core biological process for TBK1.' action: ACCEPT reason: Core biological process; TBK1 is central to innate immune signaling. supported_by: *id016 - term: id: GO:0032727 label: positive regulation of interferon-alpha production evidence_type: IDA original_reference_id: PMID:16127453 qualifier: involved_in review: summary: 'Positive regulation of interferon-alpha production: core output of TBK1/IRF7 activation in the RIG-I/MAVS (IPS-1) pathway.' action: ACCEPT reason: Core biological process; TBK1 induces IFN-alpha via IRF activation. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB - term: id: GO:0032728 label: positive regulation of interferon-beta production evidence_type: IDA original_reference_id: PMID:16127453 qualifier: involved_in review: summary: 'Positive regulation of interferon-beta production: a specific, core output of TBK1-mediated IRF3 activation.' action: ACCEPT reason: Core biological process; TBK1 induces IFN-beta via IRF3. supported_by: *id013 - term: id: GO:0045944 label: positive regulation of transcription by RNA polymerase II evidence_type: IDA original_reference_id: PMID:16127453 qualifier: involved_in review: summary: 'Positive regulation of transcription by RNA polymerase II: an indirect consequence of TBK1 activating IRF3/IRF7 transcription factors.' action: KEEP_AS_NON_CORE reason: Indirect (via IRF activation); non-core. The IFN-production terms capture the relevant output. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: leading to transcriptional activation of pro-inflammatory and antiviral genes - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19419966 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20174559 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0051219 label: phosphoprotein binding evidence_type: IPI original_reference_id: PMID:14530355 qualifier: enables review: summary: Phosphoprotein binding (TRIF/TICAM1 study). A specific interaction property; uninformative as a core function. action: KEEP_AS_NON_CORE reason: Records an interaction property; not a core function and subsumed by kinase activity. supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-1834939 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-3249378 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-918225 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-933527 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-937337 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9705010 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9705082 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9705137 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9705145 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9709831 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9709852 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9710988 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9754827 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9823910 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9823934 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9824888 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9828196 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9828209 qualifier: located_in review: summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations. action: ACCEPT reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core. supported_by: *id011 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16281057 qualifier: enables review: summary: IPI interaction annotation. TBK1 has a very large interactome (adaptors TANK/AZI2/SINTBAD, OPTN, STING1, MAVS, TRAF3, DDX3X, regulators, and many viral antagonists). These interactions are functionally important but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions but bare protein binding (GO:0005515) is uninformative per curation guidelines; the kinase activity and specific signaling-pathway annotations capture the function. supported_by: *id004 - term: id: GO:0043123 label: positive regulation of canonical NF-kappaB signal transduction evidence_type: IEP original_reference_id: PMID:12761501 qualifier: involved_in review: summary: 'Positive regulation of canonical NF-kappaB signal transduction: the founding role of TBK1 (TANK-binding kinase) as an IKK-related NF-kappaB-activating kinase.' action: ACCEPT reason: Well-supported biological process; TBK1 was identified as an NF-kappaB-activating IKK-related kinase and phosphorylates RELA/NFKBIA/IKBKB under particular conditions. supported_by: *id017 - term: id: GO:0004672 label: protein kinase activity evidence_type: NAS original_reference_id: PMID:10581243 qualifier: enables review: summary: TBK1 is a non-canonical IKK-related serine/threonine protein kinase; this is its core, extensively documented molecular function (trans-autophosphorylation at Ser172; phosphorylation of IRF3/IRF7, the adaptors MAVS/STING1/TICAM1, OPTN, SMCR8, ATG8s, etc.). action: ACCEPT reason: Core molecular function directly demonstrated by multiple experimental studies. supported_by: *id018 - term: id: GO:0007249 label: canonical NF-kappaB signal transduction evidence_type: TAS original_reference_id: PMID:10581243 qualifier: involved_in review: summary: Canonical NF-kappaB signal transduction (TAS). Records TBK1's NF-kappaB-pathway involvement; the positive-regulation term is the more informative capture. action: KEEP_AS_NON_CORE reason: Correct pathway context; subsumed by the positive-regulation-of-canonical-NF-kappaB annotation. supported_by: *id019 references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000116 title: Automatic Gene Ontology annotation based on Rhea mapping findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:10581243 title: NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Original identification of TBK1 as an IKK-related NF-kappaB-activating kinase in a TRAF2-TANK-TBK1 complex (the 'TANK-binding kinase'). - id: PMID:10783893 title: NAK is an IkappaB kinase-activating kinase. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Identifies NAK/TBK1 as an IkappaB-kinase-activating kinase; foundational for the NF-kappaB and kinase-activity annotations. - id: PMID:12761501 title: Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Large-scale screen for NF-kappaB/MAPK activators; IEP source for positive regulation of canonical NF-kappaB. - id: PMID:14530355 title: Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. findings: [] - id: PMID:14703513 title: Identification of Ser-386 of interferon regulatory factor 3 as critical target for inducible phosphorylation that determines activation. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: TBK1 phosphorylates IRF3 on Ser-386 (critical for activation); supports the core kinase activity and antiviral/type I IFN annotations. - id: PMID:14743216 title: A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. findings: [] - id: PMID:15367631 title: Activation of TBK1 and IKKvarepsilon kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunity. findings: [] - id: PMID:15485837 title: 'NAK is recruited to the TNFR1 complex in a TNFalpha-dependent manner and mediates the production of RANTES: identification of endogenous TNFR-interacting proteins by a proteomic approach.' findings: [] - id: PMID:15841462 title: Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses. findings: [] - id: PMID:16127453 title: IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. findings: [] - id: PMID:16281057 title: SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways. findings: [] - id: PMID:16306936 title: Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. findings: [] - id: PMID:17142768 title: NAK-associated protein 1 participates in both the TLR3 and the cytoplasmic pathways in type I IFN induction. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: NAP1/AZI2 (with TBK1) in TLR3 and cytoplasmic type I IFN induction; ComplexPortal source of NAS antiviral/IFN/kinase-complex annotations. - id: PMID:17568778 title: SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK. findings: [] - id: PMID:17599067 title: Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes. findings: [] - id: PMID:18307994 title: Enhanced binding of TBK1 by an optineurin mutant that causes a familial form of primary open angle glaucoma. findings: [] - id: PMID:18583960 title: The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response. findings: [] - id: PMID:18636086 title: The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. findings: [] - id: PMID:18724357 title: STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. findings: [] - id: PMID:18818105 title: The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. findings: [] - id: PMID:19153231 title: Ebola virus protein VP35 impairs the function of interferon regulatory factor-activating kinases IKKepsilon and TBK-1. findings: [] - id: PMID:19380580 title: Severe acute respiratory syndrome coronavirus M protein inhibits type I interferon production by impeding the formation of TRAF3.TANK.TBK1/IKKepsilon complex. findings: [] - id: PMID:19416887 title: ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response. findings: [] - id: PMID:19419966 title: The tyrosine kinase c-Src enhances RIG-I (retinoic acid-inducible gene I)-elicited antiviral signaling. findings: [] - id: PMID:19433799 title: ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. findings: [] - id: PMID:20098747 title: Expanding the substantial interactome of NEMO using protein microarrays. findings: [] - id: PMID:20174559 title: Optineurin negatively regulates the induction of IFNbeta in response to RNA virus infection. findings: [] - id: PMID:20562859 title: Network organization of the human autophagy system. findings: [] - id: PMID:20628368 title: Tom70 mediates activation of interferon regulatory factor 3 on mitochondria. findings: [] - id: PMID:21042276 title: Emerging roles for the non-canonical IKKs in cancer. findings: [] - id: PMID:21138416 title: Novel cross-talk within the IKK family controls innate immunity. findings: [] - id: PMID:21270402 title: TANK-binding kinase 1 attenuates PTAP-dependent retroviral budding through targeting endosomal sorting complex required for transport-I. findings: [] - id: PMID:21464307 title: IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. findings: [] - id: PMID:21617041 title: Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: TBK1 phosphorylates OPTN on Ser-177 to enhance LC3 binding and restrict cytosolic Salmonella; core xenophagy/selective-autophagy reference. - id: PMID:21813773 title: IFN-induced TPR protein IFIT3 potentiates antiviral signaling by bridging MAVS and TBK1. findings: [] - id: PMID:21903422 title: Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. findings: [] - id: PMID:21931555 title: Vaccinia virus protein C6 is a virulence factor that binds TBK-1 adaptor proteins and inhibits activation of IRF3 and IRF7. findings: [] - id: PMID:21931631 title: Functional dissection of the TBK1 molecular network. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Functional dissection of the TBK1 molecular network; defines TBK1 adaptor complexes (NAP1, TANK, SINTBAD) and antiviral roles. - id: PMID:21988832 title: Toward an understanding of the protein interaction network of the human liver. findings: [] - id: PMID:22000020 title: Activation of STAT6 by STING is critical for antiviral innate immunity. findings: [] - id: PMID:22394562 title: STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA pathway; supports cGAS-STING/IFN core function. - id: PMID:22412986 title: Activation of interferon regulatory factor 5 by site specific phosphorylation. findings: [] - id: PMID:22921120 title: TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation. findings: [] - id: PMID:22939624 title: Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. findings: [] - id: PMID:23096996 title: Hepatitis C virus NS2 protease inhibits host cell antiviral response by inhibiting IKKε and TBK1 functions. findings: [] - id: PMID:23414517 title: 'A human skeletal muscle interactome centered on proteins involved in muscular dystrophies: LGMD interactome.' findings: [] - id: PMID:23542348 title: Hepatitis C virus NS4B blocks the interaction of STING and TBK1 to evade host innate immunity. findings: [] - id: PMID:24056301 title: The deubiquitylase USP33 discriminates between RALB functions in autophagy and innate immune response. findings: [] - id: PMID:24509444 title: Suppression of innate antiviral response by severe acute respiratory syndrome coronavirus M protein is mediated through the first transmembrane domain. findings: [] - id: PMID:24560620 title: NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING. findings: [] - id: PMID:24622840 title: SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex. findings: [] - id: PMID:24643253 title: MAVS protein is attenuated by rotavirus nonstructural protein 1. findings: [] - id: PMID:24696485 title: Murine gammaherpesvirus 68 encoding open reading frame 11 targets TANK binding kinase 1 to negatively regulate the host type I interferon response. findings: [] - id: PMID:24807708 title: RIOK3 is an adaptor protein required for IRF3-mediated antiviral type I interferon production. findings: [] - id: PMID:25636800 title: Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Shows TBK1 phosphorylates the innate adaptors MAVS, STING and TRIF on the pLxIS motif to license IRF3 activation; central mechanistic reference. - id: PMID:25736436 title: WDFY1 mediates TLR3/4 signaling by recruiting TRIF. findings: [] - id: PMID:25803835 title: Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: TBK1 haploinsufficiency causes familial ALS/FTD; disease context underscoring the autophagy/innate-immune core functions. - id: PMID:27035970 title: Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: TBK1 phosphorylation of OPTN enhances Ub-chain binding and promotes mitophagy of damaged mitochondria; core selective-autophagy reference. - id: PMID:27086836 title: The TBK1-binding domain of optineurin promotes type I interferon responses. findings: [] - id: PMID:27094905 title: Middle East respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3. findings: [] - id: PMID:27103069 title: Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: TBK1 phosphorylates SMCR8 (C9orf72-SMCR8) to promote autophagosome maturation; supports positive regulation of macroautophagy. - id: PMID:27135603 title: A TRAF-like motif of the inducible costimulator ICOS controls development of germinal center TFH cells via the kinase TBK1. findings: [] - id: PMID:28011935 title: TTLL12 Inhibits the Activation of Cellular Antiviral Signaling through Interaction with VISA/MAVS. findings: [] - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] - id: PMID:28747347 title: TRIM8 Negatively Regulates TLR3/4-Mediated Innate Immune Response by Blocking TRIF-TBK1 Interaction. findings: [] - id: PMID:28871090 title: TRIM23 mediates virus-induced autophagy via activation of TBK1. findings: [] - id: PMID:29150432 title: The IKK-related kinase TBK1 activates mTORC1 directly in response to growth factors and innate immune agonists. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: TBK1 activates mTORC1 in response to growth factors/innate agonists (MTOR phosphorylation); basis for positive regulation of TORC1 (secondary role). - id: PMID:29251827 title: Quantitative Proteomics Identified TTC4 as a TBK1 Interactor and a Positive Regulator of SeV-Induced Innate Immunity. findings: [] - id: PMID:29441066 title: TANK-Binding Kinase 1 (TBK1) Isoforms Negatively Regulate Type I Interferon Induction by Inhibiting TBK1-IRF3 Interaction and IRF3 Phosphorylation. findings: [] - id: PMID:30354798 title: Ccdc61 controls centrosomal localization of Cep170 and is required for spindle assembly and symmetry. findings: [] - id: PMID:30561431 title: A protein-protein interaction map of the TNF-induced NF-κB signal transduction pathway. findings: [] - id: PMID:31390091 title: TRAF3IP3 mediates the recruitment of TRAF3 to MAVS for antiviral innate immunity. findings: [] - id: PMID:31530866 title: TBK1 Limits mTORC1 by Promoting Phosphorylation of Raptor Ser877. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: TBK1 limits mTORC1 via RPTOR Ser877 phosphorylation; basis for negative regulation of TORC1 (context-dependent, secondary role). - id: PMID:31662325 title: Phosphorylation of RAB7 by TBK1/IKKε Regulates Innate Immune Signaling in Triple-Negative Breast Cancer. findings: [] - id: PMID:31709703 title: TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls autophagosome shedding by ATG4 protease. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: TBK1 phosphorylates ATG8 proteins MAP1LC3C and GABARAPL2 to control autophagosome shedding; supports autophagy core function. - id: PMID:32209697 title: Noncanonical STAT1 phosphorylation expands its transcriptional activity into promoting LPS-induced IL-6 and IL-12p40 production. findings: [] - id: PMID:32298923 title: E3 ubiquitin ligase ASB8 negatively regulates interferon via regulating TBK1/IKKi homeostasis. findings: [] - id: PMID:32353859 title: A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. findings: [] - id: PMID:32707033 title: Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. findings: [] - id: PMID:32979938 title: Evasion of Type I Interferon by SARS-CoV-2. findings: [] - id: PMID:33060197 title: Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. findings: [] - id: PMID:33372174 title: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) membrane (M) protein inhibits type I and III interferon production by targeting RIG-I/MDA-5 signaling. findings: [] - id: PMID:33707416 title: SARS-CoV-2 non-structural protein 13 (nsp13) hijacks host deubiquitinase USP13 and counteracts host antiviral immune response. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:34084167 title: SARS-CoV-2 Membrane Protein Inhibits Type I Interferon Production Through Ubiquitin-Mediated Degradation of TBK1. findings: [] - id: PMID:34166398 title: SARS-CoV-2 viral proteins NSP1 and NSP13 inhibit interferon activation through distinct mechanisms. findings: [] - id: PMID:34524948 title: Global Proximity Interactome of the Human Macroautophagy Pathway. findings: [] - id: PMID:37219487 title: Large-scale phosphomimetic screening identifies phospho-modulated motif-based protein interactions. findings: [] - id: PMID:37403426 title: 'MicroRNA-4691-3p inhibits the inflammatory response by targeting STING in human dental pulp cells: A laboratory investigation.' findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: miR-4691-3p/STING study used as TAS source for cGAS/STING pathway and kinase-activity terms; peripheral to direct TBK1 characterization. - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] - id: Reactome:R-HSA-1606327 title: 'Phosphorylation and release of IRF3 ' findings: [] - id: Reactome:R-HSA-166245 title: 'Phosphorylation of IRF-3/IRF7 and their release from the activated TLR complex ' findings: [] - id: Reactome:R-HSA-166271 title: IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR4 findings: [] - id: Reactome:R-HSA-1834939 title: STING recruits TBK1 and IRF3 findings: [] - id: Reactome:R-HSA-1834941 title: STING mediated induction of host immune responses findings: [] - id: Reactome:R-HSA-2396002 title: TBK1 is phosphorylated within STING:TBK1:IRF3 complex findings: [] - id: Reactome:R-HSA-2396007 title: IRF3 is phosphorylated by TBK1 findings: [] - id: Reactome:R-HSA-3249371 title: TBK1 phosphorylates STAT6 at Ser407 findings: [] - id: Reactome:R-HSA-3249378 title: STING recruits TBK1 and STAT6 findings: [] - id: Reactome:R-HSA-3249386 title: DTX4 ubiquitinates p-S172-TBK1 within NLRP4:DTX4:dsDNA:ZBP1:TBK1 findings: [] - id: Reactome:R-HSA-3249390 title: TBK1 is phosphorylated within STING:TBK1:STAT6 complex findings: [] - id: Reactome:R-HSA-3249392 title: NLRP4 and DTX4 associate with p-S172-TBK1 within STING:TBK1:IRF3 findings: [] - id: Reactome:R-HSA-3270619 title: IRF3-mediated induction of type I IFN findings: [] - id: Reactome:R-HSA-5205685 title: PINK1-PRKN Mediated Mitophagy findings: [] - id: Reactome:R-HSA-8948703 title: NLRP4 and DTX4 associate with p-S172-TBK1 within dsDNA:ZBP1:TBK1 findings: [] - id: Reactome:R-HSA-8948709 title: DTX4 ubiquitinates p-S172-TBK1 within NLRP4:DTX4:STING:TBK1:IRF3 findings: [] - id: Reactome:R-HSA-9008684 title: TBK1 phosphorylation findings: [] - id: Reactome:R-HSA-9013978 title: 'Phosphorylation of IRF-3/IRF7 and their release from the activated TLR3 complex ' findings: [] - id: Reactome:R-HSA-9013979 title: IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR3 findings: [] - id: Reactome:R-HSA-918225 title: TBK1/IKK epsilon complex interacts with MAVS bound TRAF3 findings: [] - id: Reactome:R-HSA-918229 title: Phosphorylation and release of IRF3/IRF7 findings: [] - id: Reactome:R-HSA-918232 title: Recruitment of IRF3,IRF7 findings: [] - id: Reactome:R-HSA-933525 title: Phosphorylation and release of IRF7 findings: [] - id: Reactome:R-HSA-933527 title: Recruitment of TBK1/IKK epsilon complex to TANK:TRAF6 findings: [] - id: Reactome:R-HSA-933538 title: Recruitment of IRF7 to TRAF6 findings: [] - id: Reactome:R-HSA-937337 title: TAX1BP1:A20 inhibit TBK1/IKKi K63-polyubiquitination findings: [] - id: Reactome:R-HSA-9679819 title: TBK1 binds amlexanox findings: [] - id: Reactome:R-HSA-9705010 title: SARS-CoV-2 nsp6 binds TBK1 findings: [] - id: Reactome:R-HSA-9705082 title: SARS-CoV-2 nsp13 binds TBK1 findings: [] - id: Reactome:R-HSA-9705137 title: TBK1 or IKBKE forms homodimers findings: [] - id: Reactome:R-HSA-9705145 title: TBK1, IKBKE form homodimers findings: [] - id: Reactome:R-HSA-9705320 title: TBK1, IKBKE are autophosphorylated at Ser172 findings: [] - id: Reactome:R-HSA-9705323 title: Phosphorylation of TBK1/IKBKE findings: [] - id: Reactome:R-HSA-9709831 title: HSP90 binds TBK1 and IRF3 findings: [] - id: Reactome:R-HSA-9709852 title: MAVS:TOMM70 recruits HSP90:TBK1:IRF3 findings: [] - id: Reactome:R-HSA-9710988 title: SARS-CoV-1 M protein interacts with TBK1/IKBKE findings: [] - id: Reactome:R-HSA-9754827 title: SARS-CoV-2 M binds TBK1 findings: [] - id: Reactome:R-HSA-9817397 title: TBK1, IKBKE phosphorylate RIPK1 at T189 findings: [] - id: Reactome:R-HSA-9817411 title: TBK1, IKBKE binds Met1-polyUb within the TNFR1 complex findings: [] - id: Reactome:R-HSA-9823904 title: TBK1 is ubiquitinated within TBK1:K63polyUb-TANK:K63polyUb-TRAF3:TRIF:activated TLR4 findings: [] - id: Reactome:R-HSA-9823906 title: TBK1 is phosphorylated within the activated TLR4 complex findings: [] - id: Reactome:R-HSA-9823910 title: 'Recruitment of TBK1 to K63polyUb-TANK:K63polyUb-TRAF3:TRIF:activated TLR4 ' findings: [] - id: Reactome:R-HSA-9823934 title: OPTN binds TBK1 within the activated TLR4 complex findings: [] - id: Reactome:R-HSA-9824888 title: OPTN, TBK1 bind ubiquitinated MOM proteins findings: [] - id: Reactome:R-HSA-9824892 title: MAP1LC3B binds p-S-OPTN bound to Ub-mitochondria findings: [] - id: Reactome:R-HSA-9824894 title: TBK1 is phosphorylated within TBK1:OPTN:Ub-mitochondrial proteins findings: [] - id: Reactome:R-HSA-9824897 title: p-S-TBK1 phosphorylates OPTN findings: [] - id: Reactome:R-HSA-9828196 title: 'TBK1 binds K63-pUb-TANK:K63-pUb-TRAF3:TRIF:activated TLR3 ' findings: [] - id: Reactome:R-HSA-9828200 title: TBK1 is ubiquitinated within TBK1:K63polyUb-TANK:K63polyUb-TRAF3:TRIF:activated TLR3 findings: [] - id: Reactome:R-HSA-9828205 title: TBK1 is phosphorylated within the activated TLR3 complex findings: [] - id: Reactome:R-HSA-9828209 title: OPTN binds TBK1 within the activated TLR3 complex findings: [] - id: Reactome:R-HSA-9840807 title: OPTN binds ATG9A findings: [] core_functions: - description: Acts as a non-canonical IKK-related protein serine/threonine kinase, phosphorylating the innate adaptors MAVS, STING1 and TICAM1/TRIF and the transcription factors IRF3/IRF7 to induce type I interferons in the antiviral innate immune response, including the cGAS-STING DNA-sensing pathway. molecular_function: id: GO:0004674 label: protein serine/threonine kinase activity supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 locations: - id: GO:0005829 label: cytosol directly_involved_in: - id: GO:0140374 label: antiviral innate immune response - id: GO:0032481 label: positive regulation of type I interferon production - description: Drives selective autophagy by phosphorylating autophagy cargo receptors (e.g. OPTN/optineurin on Ser177) and autophagy machinery (SMCR8, ATG8 proteins), enhancing receptor ubiquitin/LC3 binding and autophagosome maturation to mediate mitophagy and antibacterial xenophagy. molecular_function: id: GO:0004674 label: protein serine/threonine kinase activity supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy locations: - id: GO:0005829 label: cytosol directly_involved_in: - id: GO:0016239 label: positive regulation of macroautophagy - id: GO:1904417 label: positive regulation of xenophagy - description: Functions as an NF-kappaB-activating IKK-related kinase, assembling with the adaptor TANK and phosphorylating RELA/NFKBIA/IKBKB under particular conditions to promote NF-kappaB-dependent gene expression. molecular_function: id: GO:0004674 label: protein serine/threonine kinase activity supported_by: - reference_id: file:human/TBK1/TBK1-uniprot.txt supporting_text: functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus locations: - id: GO:0005829 label: cytosol directly_involved_in: - id: GO:0043123 label: positive regulation of canonical NF-kappaB signal transduction suggested_questions: - question: How is TBK1's substrate selection partitioned between its antiviral/IFN-induction outputs (IRF3/IRF7, STING1/MAVS/TRIF) and its selective-autophagy outputs (OPTN, NDP52, TAX1BP1, SMCR8, ATG8s) within different signaling complexes and adaptors? - question: Given that TBK1 both activates and limits mTORC1 depending on stimulus, what determines the directionality of its mTOR regulation, and how does this intersect with its core innate-immune and autophagy roles? suggested_experiments: - description: Use TBK1-knockout cells reconstituted with wild-type, kinase-dead (K38A), or Ser172-phospho-deficient TBK1, combined with phosphoproteomics under cGAS-STING, RIG-I/MAVS, TLR3/4, and mitophagy/xenophagy stimuli, to map the stimulus-specific TBK1 substrate repertoire and distinguish core IFN-induction from autophagy outputs. - description: Reconstitute IRF3 and OPTN phosphorylation in vitro with purified TBK1 and the adaptors STING1/MAVS or autophagy receptors to test how adaptor pLxIS-motif phosphorylation and TBK1 oligomerization license downstream substrate phosphorylation.