TBK1

UniProt ID: Q9UHD2
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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 Review

GO Term Evidence Action Reason
GO:0005737 cytoplasm
IBA
GO_REF:0000033 		ACCEPT
Summary: Cytoplasm: the core compartment where TBK1 assembles into signaling complexes and phosphorylates its substrates.
Reason: Core cytoplasmic localization, experimentally supported.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0004674 protein serine/threonine kinase activity
IBA
GO_REF:0000033 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0002218 activation of innate immune response
IBA
GO_REF:0000033 		ACCEPT
Summary: Activation of innate immune response: core process; TBK1 activation is a central node in innate antiviral signaling.
Reason: Core biological process directly supported by experimental evidence.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0032481 positive regulation of type I interferon production
IBA
GO_REF:0000033 		ACCEPT
Summary: Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.
Reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0002218 activation of innate immune response
IEA
GO_REF:0000117 		ACCEPT
Summary: Activation of innate immune response: core process; TBK1 activation is a central node in innate antiviral signaling.
Reason: Core biological process directly supported by experimental evidence.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0004672 protein kinase activity
IEA
GO_REF:0000002 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0004674 protein serine/threonine kinase activity
IEA
GO_REF:0000120 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0005524 ATP binding
IEA
GO_REF:0000002 		ACCEPT
Summary: ATP binding by the kinase domain, part of the catalytic mechanism of TBK1.
Reason: Correct and integral to the core protein kinase activity.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0005737 cytoplasm
IEA
GO_REF:0000044 		ACCEPT
Summary: Cytoplasm: the core compartment where TBK1 assembles into signaling complexes and phosphorylates its substrates.
Reason: Core cytoplasmic localization, experimentally supported.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0006952 defense response
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: Defense response: a generic parent of TBK1's specific antiviral/innate-immune role.
Reason: Correct but generic; the specific antiviral-innate-immune-response and type-I-IFN-production terms capture the core function more precisely.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0016239 positive regulation of macroautophagy
IEA
GO_REF:0000117 		ACCEPT
Summary: Positive regulation of macroautophagy: core process; TBK1 phosphorylates autophagy receptors (OPTN Ser177) and SMCR8 to promote selective autophagy and autophagosome maturation.
Reason: Core biological process directly demonstrated (OPTN, SMCR8, ATG8 phosphorylation).
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy
GO:0032008 positive regulation of TOR signaling
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: Positive regulation of TOR signaling (IEA): generic mTOR-pathway parent; secondary/pleiotropic.
Reason: Generic and context-dependent; non-core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
activates mTORC1 in response to growth factors by catalyzing phosphorylation of MTOR
GO:0032728 positive regulation of interferon-beta production
IEA
GO_REF:0000117 		ACCEPT
Summary: Positive regulation of interferon-beta production: a specific, core output of TBK1-mediated IRF3 activation.
Reason: Core biological process; TBK1 induces IFN-beta via IRF3.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB
GO:0043123 positive regulation of canonical NF-kappaB signal transduction
IEA
GO_REF:0000117 		ACCEPT
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.
Reason: Well-supported biological process; TBK1 was identified as an NF-kappaB-activating IKK-related kinase and phosphorylates RELA/NFKBIA/IKBKB under particular conditions.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0051707 response to other organism
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: Response to other organism: a generic parent of TBK1's specific antiviral/innate-immune role.
Reason: Correct but generic; the specific antiviral-innate-immune-response and type-I-IFN-production terms capture the core function more precisely.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0106310 protein serine kinase activity
IEA
GO_REF:0000116 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0005515 protein binding
IPI
PMID:14743216
A physical and functional map of the human TNF-alpha/NF-kapp... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:15841462
Interaction between the HCV NS3 protein and the host TBK1 pr... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:16306936
Critical role of TRAF3 in the Toll-like receptor-dependent a... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:17568778
SINTBAD, a novel component of innate antiviral immunity, sha... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:17599067
Involvement of the ubiquitin-like domain of TBK1/IKK-i kinas... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:18307994
Enhanced binding of TBK1 by an optineurin mutant that causes... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:18583960
The DEAD-box helicase DDX3X is a critical component of the T... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:18724357
STING is an endoplasmic reticulum adaptor that facilitates i... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:19153231
Ebola virus protein VP35 impairs the function of interferon ... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:19380580
Severe acute respiratory syndrome coronavirus M protein inhi... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:19416887
ISG56 is a negative-feedback regulator of virus-triggered si... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:19433799
ERIS, an endoplasmic reticulum IFN stimulator, activates inn... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:20098747
Expanding the substantial interactome of NEMO using protein ... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:20562859
Network organization of the human autophagy system. 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:21903422
Mapping a dynamic innate immunity protein interaction networ... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:21931555
Vaccinia virus protein C6 is a virulence factor that binds T... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:21988832
Toward an understanding of the protein interaction network o... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:22000020
Activation of STAT6 by STING is critical for antiviral innat... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:22939624
Quantitative analysis of HSP90-client interactions reveals p... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:23096996
Hepatitis C virus NS2 protease inhibits host cell antiviral ... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:23414517
A human skeletal muscle interactome centered on proteins inv... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:23542348
Hepatitis C virus NS4B blocks the interaction of STING and T... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:24509444
Suppression of innate antiviral response by severe acute res... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:24622840
SARS coronavirus papain-like protease inhibits the type I in... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:24643253
MAVS protein is attenuated by rotavirus nonstructural protei... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:24696485
Murine gammaherpesvirus 68 encoding open reading frame 11 ta... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:24807708
RIOK3 is an adaptor protein required for IRF3-mediated antiv... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:25803835
Haploinsufficiency of TBK1 causes familial ALS and fronto-te... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:27086836
The TBK1-binding domain of optineurin promotes type I interf... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:27094905
Middle East respiratory syndrome coronavirus M protein suppr... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:27135603
A TRAF-like motif of the inducible costimulator ICOS control... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:29251827
Quantitative Proteomics Identified TTC4 as a TBK1 Interactor... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:30561431
A protein-protein interaction map of the TNF-induced NF-κB s... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:32353859
A SARS-CoV-2 protein interaction map reveals targets for dru... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:32707033
Kinase Interaction Network Expands Functional and Disease Ro... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:32979938
Evasion of Type I Interferon by SARS-CoV-2. 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:33060197
Comparative host-coronavirus protein interaction networks re... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:33372174
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:33707416
SARS-CoV-2 non-structural protein 13 (nsp13) hijacks host de... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:34084167
SARS-CoV-2 Membrane Protein Inhibits Type I Interferon Produ... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:34166398
SARS-CoV-2 viral proteins NSP1 and NSP13 inhibit interferon ... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:34524948
Global Proximity Interactome of the Human Macroautophagy Pat... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:37219487
Large-scale phosphomimetic screening identifies phospho-modu... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:40205054
Multimodal cell maps as a foundation for structural and func... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0003676 nucleic acid binding
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
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.
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).
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0010629 negative regulation of gene expression
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
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.
Reason: Overly generic electronic ortholog transfer that does not reflect the documented positive, IRF-driven transcriptional role; flagged as over-annotation.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB
GO:0019903 protein phosphatase binding
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Protein phosphatase binding, inferred by orthology (IEA/ISS). Relates to regulation of TBK1 phosphorylation status; not a core function.
Reason: Orthology-based interaction property; non-core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0042802 identical protein binding
IEA
GO_REF:0000107 		KEEP AS NON CORE
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.
Reason: Real homodimerization but the term is uninformative; the coiled-coil-mediated dimerization is better described at the structural level.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
and a C-terminal coiled-coil region mediating homodimerization.
GO:0060340 positive regulation of type I interferon-mediated signaling pathway
IEA
GO_REF:0000107 		KEEP AS NON CORE
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.
Reason: Orthology-based; imprecise relative to TBK1's induction role. Non-core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:1904417 positive regulation of xenophagy
IEA
GO_REF:0000107 		ACCEPT
Summary: Positive regulation of xenophagy: TBK1 phosphorylates OPTN on Ser177 to drive selective autophagy of cytosolic bacteria (e.g. Salmonella).
Reason: Core biological process directly demonstrated for antibacterial (xeno)phagy.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy
GO:1904515 positive regulation of TORC2 signaling
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Positive regulation of TORC2 signaling (ISS/IEA, by orthology): TBK1 promotes mTORC2-dependent AKT1 activation. Secondary/pleiotropic role.
Reason: Orthology-based, secondary role; non-core relative to innate immunity/autophagy.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Acts as a positive regulator of the mTORC2 complex by mediating phosphorylation of MTOR
GO:0016236 macroautophagy
TAS
Reactome:R-HSA-5205685 		KEEP AS NON CORE
Summary: Macroautophagy (Reactome PINK1-PRKN mitophagy TAS). A generic parent of TBK1's specific positive-regulatory autophagy role.
Reason: Correct but generic; the positive-regulation-of-macroautophagy/xenophagy terms capture the core function.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy
GO:0032481 positive regulation of type I interferon production
TAS
Reactome:R-HSA-1834941 		ACCEPT
Summary: Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.
Reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0032481 positive regulation of type I interferon production
TAS
Reactome:R-HSA-3270619 		ACCEPT
Summary: Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.
Reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0004674 protein serine/threonine kinase activity
EXP
PMID:27035970
Phosphorylation of OPTN by TBK1 enhances its binding to Ub c... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0004674 protein serine/threonine kinase activity
TAS
Reactome:R-HSA-2396007 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0004674 protein serine/threonine kinase activity
TAS
Reactome:R-HSA-3249371 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0004674 protein serine/threonine kinase activity
TAS
Reactome:R-HSA-933525 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0005654 nucleoplasm
IDA
GO_REF:0000052 		KEEP AS NON CORE
Summary: Nucleoplasm (IDA, immunofluorescence/HPA): a minor pool. TBK1 is predominantly cytoplasmic and acts there.
Reason: Minor/secondary localization; the dominant functional pool is cytoplasmic.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005737 cytoplasm
EXP
PMID:15485837
NAK is recruited to the TNFR1 complex in a TNFalpha-dependen... 		ACCEPT
Summary: Cytoplasm: the core compartment where TBK1 assembles into signaling complexes and phosphorylates its substrates.
Reason: Core cytoplasmic localization, experimentally supported.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005737 cytoplasm
EXP
PMID:32298923
E3 ubiquitin ligase ASB8 negatively regulates interferon via... 		ACCEPT
Summary: Cytoplasm: the core compartment where TBK1 assembles into signaling complexes and phosphorylates its substrates.
Reason: Core cytoplasmic localization, experimentally supported.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0106310 protein serine kinase activity
EXP
PMID:10783893
NAK is an IkappaB kinase-activating kinase. 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0106310 protein serine kinase activity
EXP
PMID:14703513
Identification of Ser-386 of interferon regulatory factor 3 ... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0106310 protein serine kinase activity
EXP
PMID:15367631
Activation of TBK1 and IKKvarepsilon kinases by vesicular st... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0106310 protein serine kinase activity
EXP
PMID:18583960
The DEAD-box helicase DDX3X is a critical component of the T... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0106310 protein serine kinase activity
EXP
PMID:21138416
Novel cross-talk within the IKK family controls innate immun... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0106310 protein serine kinase activity
EXP
PMID:21270402
TANK-binding kinase 1 attenuates PTAP-dependent retroviral b... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0106310 protein serine kinase activity
EXP
PMID:21464307
IkappaB kinase epsilon and TANK-binding kinase 1 activate AK... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0106310 protein serine kinase activity
EXP
PMID:21617041
Phosphorylation of the autophagy receptor optineurin restric... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0106310 protein serine kinase activity
EXP
PMID:25636800
Phosphorylation of innate immune adaptor proteins MAVS, STIN... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0106310 protein serine kinase activity
EXP
PMID:29150432
The IKK-related kinase TBK1 activates mTORC1 directly in res... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0106310 protein serine kinase activity
EXP
PMID:31530866
TBK1 Limits mTORC1 by Promoting Phosphorylation of Raptor Se... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0106310 protein serine kinase activity
EXP
PMID:31709703
TBK1-mediated phosphorylation of LC3C and GABARAP-L2 control... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0051607 defense response to virus
NAS
PMID:17142768
NAK-associated protein 1 participates in both the TLR3 and t... 		ACCEPT
Summary: Defense response to virus: a core, well-supported biological process; TBK1 is essential for antiviral defense via IRF3/type I IFN.
Reason: Core biological process strongly supported across the literature.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0051607 defense response to virus
NAS
PMID:21931631
Functional dissection of the TBK1 molecular network. 		ACCEPT
Summary: Defense response to virus: a core, well-supported biological process; TBK1 is essential for antiviral defense via IRF3/type I IFN.
Reason: Core biological process strongly supported across the literature.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0051607 defense response to virus
NAS
PMID:24622840
SARS coronavirus papain-like protease inhibits the type I in... 		ACCEPT
Summary: Defense response to virus: a core, well-supported biological process; TBK1 is essential for antiviral defense via IRF3/type I IFN.
Reason: Core biological process strongly supported across the literature.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0060337 type I interferon-mediated signaling pathway
NAS
PMID:17142768
NAK-associated protein 1 participates in both the TLR3 and t... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0060337 type I interferon-mediated signaling pathway
NAS
PMID:21931631
Functional dissection of the TBK1 molecular network. 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:1902554 serine/threonine protein kinase complex
NAS
PMID:17142768
NAK-associated protein 1 participates in both the TLR3 and t... 		ACCEPT
Summary: Serine/threonine protein kinase complex: TBK1 functions within kinase complexes (e.g. the TBK1-IKKepsilon-NAP1/TANK/SINTBAD complexes).
Reason: Core cellular component; TBK1 acts as part of ser/thr kinase complexes with its adaptors.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes
GO:1902554 serine/threonine protein kinase complex
NAS
PMID:21931631
Functional dissection of the TBK1 molecular network. 		ACCEPT
Summary: Serine/threonine protein kinase complex: TBK1 functions within kinase complexes (e.g. the TBK1-IKKepsilon-NAP1/TANK/SINTBAD complexes).
Reason: Core cellular component; TBK1 acts as part of ser/thr kinase complexes with its adaptors.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes
GO:1902554 serine/threonine protein kinase complex
NAS
PMID:24622840
SARS coronavirus papain-like protease inhibits the type I in... 		ACCEPT
Summary: Serine/threonine protein kinase complex: TBK1 functions within kinase complexes (e.g. the TBK1-IKKepsilon-NAP1/TANK/SINTBAD complexes).
Reason: Core cellular component; TBK1 acts as part of ser/thr kinase complexes with its adaptors.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes
GO:0005515 protein binding
IPI
PMID:18818105
The adaptor protein MITA links virus-sensing receptors to IR... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0002753 cytoplasmic pattern recognition receptor signaling pathway
IDA
PMID:29441066
TANK-Binding Kinase 1 (TBK1) Isoforms Negatively Regulate Ty... 		ACCEPT
Summary: Cytoplasmic pattern recognition receptor signaling pathway: TBK1 functions downstream of cytoplasmic RNA/DNA sensors (RIG-I/MDA5-MAVS, cGAS-STING).
Reason: Core biological process; TBK1 transduces cytoplasmic PRR signals to IRF3.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1
GO:0004674 protein serine/threonine kinase activity
IDA
PMID:14703513
Identification of Ser-386 of interferon regulatory factor 3 ... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0005737 cytoplasm
IDA
PMID:14703513
Identification of Ser-386 of interferon regulatory factor 3 ... 		ACCEPT
Summary: Cytoplasm: the core compartment where TBK1 assembles into signaling complexes and phosphorylates its substrates.
Reason: Core cytoplasmic localization, experimentally supported.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding
IPI
PMID:22412986
Activation of interferon regulatory factor 5 by site specifi... 		KEEP AS NON CORE
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.
Reason: Records an IRF (substrate) interaction; subsumed by the core kinase activity and IFN-production annotations.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7
GO:0106310 protein serine kinase activity
IDA
PMID:22412986
Activation of interferon regulatory factor 5 by site specifi... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0140896 cGAS/STING signaling pathway
TAS
PMID:37403426
MicroRNA-4691-3p inhibits the inflammatory response by targe... 		ACCEPT
Summary: cGAS/STING signaling pathway: TBK1 is the kinase recruited by activated STING1 that phosphorylates STING1 and IRF3 in the cytosolic DNA-sensing pathway.
Reason: Core biological process; TBK1 is an essential kinase of the cGAS-STING axis.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1
GO:0004674 protein serine/threonine kinase activity
ISS
GO_REF:0000024 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:1904515 positive regulation of TORC2 signaling
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Positive regulation of TORC2 signaling (ISS/IEA, by orthology): TBK1 promotes mTORC2-dependent AKT1 activation. Secondary/pleiotropic role.
Reason: Orthology-based, secondary role; non-core relative to innate immunity/autophagy.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Acts as a positive regulator of the mTORC2 complex by mediating phosphorylation of MTOR
GO:0005829 cytosol
IDA
PMID:21813773
IFN-induced TPR protein IFIT3 potentiates antiviral signalin... 		ACCEPT
Summary: Cytosol: the core subcellular location of TBK1 signaling activity.
Reason: Core cytosolic localization consistent with experimental cytoplasmic localization.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0032481 positive regulation of type I interferon production
IDA
PMID:25636800
Phosphorylation of innate immune adaptor proteins MAVS, STIN... 		ACCEPT
Summary: Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.
Reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0061470 T follicular helper cell differentiation
IDA
PMID:27135603
A TRAF-like motif of the inducible costimulator ICOS control... 		KEEP AS NON CORE
Summary: T follicular helper cell differentiation: TBK1 participates with ICOS in TFH/TFR cell differentiation. A specialized, developmental/immunological role.
Reason: Specialized pleiotropic role; non-core relative to the kinase's central innate-immune/autophagy functions.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
participates in the differentiation of T follicular regulatory cells together with the receptor ICOS
GO:0005515 protein binding
IPI
PMID:32209697
Noncanonical STAT1 phosphorylation expands its transcription... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0140374 antiviral innate immune response
IDA
PMID:14703513
Identification of Ser-386 of interferon regulatory factor 3 ... 		ACCEPT
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.
Reason: Core biological process directly demonstrated; TBK1 is a master kinase of antiviral innate immunity.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0004674 protein serine/threonine kinase activity
TAS
PMID:37403426
MicroRNA-4691-3p inhibits the inflammatory response by targe... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0005829 cytosol
TAS
PMID:37403426
MicroRNA-4691-3p inhibits the inflammatory response by targe... 		ACCEPT
Summary: Cytosol: the core subcellular location of TBK1 signaling activity.
Reason: Core cytosolic localization consistent with experimental cytoplasmic localization.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0004674 protein serine/threonine kinase activity
IDA
PMID:22394562
STING specifies IRF3 phosphorylation by TBK1 in the cytosoli... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0032481 positive regulation of type I interferon production
IDA
PMID:22394562
STING specifies IRF3 phosphorylation by TBK1 in the cytosoli... 		ACCEPT
Summary: Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.
Reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0140374 antiviral innate immune response
IDA
PMID:22394562
STING specifies IRF3 phosphorylation by TBK1 in the cytosoli... 		ACCEPT
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.
Reason: Core biological process directly demonstrated; TBK1 is a master kinase of antiviral innate immunity.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0002218 activation of innate immune response
IDA
PMID:25636800
Phosphorylation of innate immune adaptor proteins MAVS, STIN... 		ACCEPT
Summary: Activation of innate immune response: core process; TBK1 activation is a central node in innate antiviral signaling.
Reason: Core biological process directly supported by experimental evidence.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0004674 protein serine/threonine kinase activity
IDA
PMID:29150432
The IKK-related kinase TBK1 activates mTORC1 directly in res... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0004674 protein serine/threonine kinase activity
IDA
PMID:31530866
TBK1 Limits mTORC1 by Promoting Phosphorylation of Raptor Se... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:1904262 negative regulation of TORC1 signaling
IDA
PMID:31530866
TBK1 Limits mTORC1 by Promoting Phosphorylation of Raptor Se... 		KEEP AS NON CORE
Summary: Negative regulation of TORC1 signaling: TBK1 limits mTORC1 by phosphorylating RPTOR (Ser877). A context-dependent, secondary role opposite to its TORC1-activating role.
Reason: Real but context-dependent/pleiotropic; non-core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
it limits the mTORC1 complex by promoting phosphorylation of RPTOR
GO:1904263 positive regulation of TORC1 signaling
IDA
PMID:29150432
The IKK-related kinase TBK1 activates mTORC1 directly in res... 		KEEP AS NON CORE
Summary: Positive regulation of TORC1 signaling: TBK1 activates mTORC1 in response to growth factors (MTOR phosphorylation). A context-dependent, secondary role.
Reason: Real but context-dependent and pleiotropic; opposite TORC1 effects are reported depending on stimulus. Non-core relative to innate immunity/autophagy.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
activates mTORC1 in response to growth factors by catalyzing phosphorylation of MTOR
GO:0034142 toll-like receptor 4 signaling pathway
IDA
PMID:28747347
TRIM8 Negatively Regulates TLR3/4-Mediated Innate Immune Res... 		KEEP AS NON CORE
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.
Reason: Correct pathway context; the antiviral-innate-immune and type-I-IFN terms are the core capture.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors
GO:0032481 positive regulation of type I interferon production
IDA
PMID:14703513
Identification of Ser-386 of interferon regulatory factor 3 ... 		ACCEPT
Summary: Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.
Reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0004674 protein serine/threonine kinase activity
IDA
PMID:22921120
TBK-1 promotes autophagy-mediated antimicrobial defense by c... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0010508 positive regulation of autophagy
IDA
PMID:28871090
TRIM23 mediates virus-induced autophagy via activation of TB... 		ACCEPT
Summary: Positive regulation of autophagy: core process driven by TBK1 phosphorylation of autophagy machinery and receptors.
Reason: Core biological process directly demonstrated.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy
GO:0004674 protein serine/threonine kinase activity
IDA
PMID:29441066
TANK-Binding Kinase 1 (TBK1) Isoforms Negatively Regulate Ty... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0032728 positive regulation of interferon-beta production
IDA
PMID:31390091
TRAF3IP3 mediates the recruitment of TRAF3 to MAVS for antiv... 		ACCEPT
Summary: Positive regulation of interferon-beta production: a specific, core output of TBK1-mediated IRF3 activation.
Reason: Core biological process; TBK1 induces IFN-beta via IRF3.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB
GO:0032481 positive regulation of type I interferon production
IDA
PMID:29441066
TANK-Binding Kinase 1 (TBK1) Isoforms Negatively Regulate Ty... 		ACCEPT
Summary: Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.
Reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0004674 protein serine/threonine kinase activity
IDA
PMID:31709703
TBK1-mediated phosphorylation of LC3C and GABARAP-L2 control... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0005829 cytosol
TAS
Reactome:R-HSA-9823904 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9828200 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005515 protein binding
IPI
PMID:20628368
Tom70 mediates activation of interferon regulatory factor 3 ... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:30354798
Ccdc61 controls centrosomal localization of Cep170 and is re... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0004674 protein serine/threonine kinase activity
IDA
PMID:31662325
Phosphorylation of RAB7 by TBK1/IKKε Regulates Innate Immune... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0005737 cytoplasm
IDA
PMID:29251827
Quantitative Proteomics Identified TTC4 as a TBK1 Interactor... 		ACCEPT
Summary: Cytoplasm: the core compartment where TBK1 assembles into signaling complexes and phosphorylates its substrates.
Reason: Core cytoplasmic localization, experimentally supported.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005515 protein binding
IPI
PMID:28011935
TTLL12 Inhibits the Activation of Cellular Antiviral Signali... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0004674 protein serine/threonine kinase activity
IDA
PMID:25636800
Phosphorylation of innate immune adaptor proteins MAVS, STIN... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0018105 peptidyl-serine phosphorylation
IDA
PMID:25636800
Phosphorylation of innate immune adaptor proteins MAVS, STIN... 		KEEP AS NON CORE
Summary: Peptidyl-serine phosphorylation: a generic process description of TBK1's kinase activity.
Reason: Correct but generic; the protein serine/threonine kinase activity (MF) and the specific signaling-pathway terms are more informative.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0018107 peptidyl-threonine phosphorylation
IDA
PMID:25636800
Phosphorylation of innate immune adaptor proteins MAVS, STIN... 		KEEP AS NON CORE
Summary: Peptidyl-threonine phosphorylation: a generic process description of TBK1's kinase activity.
Reason: Correct but generic; the protein serine/threonine kinase activity (MF) and the specific signaling-pathway terms are more informative.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0032479 regulation of type I interferon production
IDA
PMID:25636800
Phosphorylation of innate immune adaptor proteins MAVS, STIN... 		ACCEPT
Summary: Regulation of type I interferon production: core regulatory role of TBK1 via adaptor and IRF3 phosphorylation.
Reason: Core biological process; consistent with the positive-regulation-of-type-I-IFN annotations.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0045087 innate immune response
IDA
PMID:25636800
Phosphorylation of innate immune adaptor proteins MAVS, STIN... 		ACCEPT
Summary: Innate immune response: core biological process for TBK1.
Reason: Core biological process; TBK1 is central to innate immune signaling.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0019903 protein phosphatase binding
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Protein phosphatase binding, inferred by orthology (IEA/ISS). Relates to regulation of TBK1 phosphorylation status; not a core function.
Reason: Orthology-based interaction property; non-core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0005829 cytosol
TAS
Reactome:R-HSA-9008684 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0004674 protein serine/threonine kinase activity
IDA
PMID:27103069
Loss of C9ORF72 impairs autophagy and synergizes with polyQ ... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0005515 protein binding
IPI
PMID:27103069
Loss of C9ORF72 impairs autophagy and synergizes with polyQ ... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0006468 protein phosphorylation
IDA
PMID:27103069
Loss of C9ORF72 impairs autophagy and synergizes with polyQ ... 		KEEP AS NON CORE
Summary: Protein phosphorylation: a generic process description of TBK1's kinase activity.
Reason: Correct but generic; the protein serine/threonine kinase activity (MF) and the specific signaling-pathway terms are more informative.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0005515 protein binding
IPI
PMID:24560620
NLRC3, a member of the NLR family of proteins, is a negative... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0016239 positive regulation of macroautophagy
IDA
PMID:27103069
Loss of C9ORF72 impairs autophagy and synergizes with polyQ ... 		ACCEPT
Summary: Positive regulation of macroautophagy: core process; TBK1 phosphorylates autophagy receptors (OPTN Ser177) and SMCR8 to promote selective autophagy and autophagosome maturation.
Reason: Core biological process directly demonstrated (OPTN, SMCR8, ATG8 phosphorylation).
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy
GO:0005515 protein binding
IPI
PMID:25736436
WDFY1 mediates TLR3/4 signaling by recruiting TRIF. 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0004674 protein serine/threonine kinase activity
IDA
PMID:25803835
Haploinsufficiency of TBK1 causes familial ALS and fronto-te... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0005515 protein binding
IPI
PMID:24056301
The deubiquitylase USP33 discriminates between RALB function... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005829 cytosol
TAS
Reactome:R-HSA-3249386 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-8948709 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-1606327 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-166245 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-166271 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-2396002 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-2396007 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-3249371 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-3249390 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-3249392 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-8948703 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9013978 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9013979 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-918229 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-918232 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-933525 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-933538 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9679819 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9705320 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9705323 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9817397 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9817411 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9823906 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9824892 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9824894 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9824897 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9828205 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9840807 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005515 protein binding
IPI
PMID:21813773
IFN-induced TPR protein IFIT3 potentiates antiviral signalin... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005737 cytoplasm
IDA
PMID:21813773
IFN-induced TPR protein IFIT3 potentiates antiviral signalin... 		ACCEPT
Summary: Cytoplasm: the core compartment where TBK1 assembles into signaling complexes and phosphorylates its substrates.
Reason: Core cytoplasmic localization, experimentally supported.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005515 protein binding
IPI
PMID:18636086
The tumour suppressor CYLD is a negative regulator of RIG-I-... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0004674 protein serine/threonine kinase activity
TAS
PMID:21042276
Emerging roles for the non-canonical IKKs in cancer. 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0006954 inflammatory response
TAS
PMID:21042276
Emerging roles for the non-canonical IKKs in cancer. 		KEEP AS NON CORE
Summary: Inflammatory response (review TAS). A broad downstream consequence of TBK1 signaling.
Reason: Broad/secondary process; the specific IFN and NF-kappaB signaling terms are more informative.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0007249 canonical NF-kappaB signal transduction
TAS
PMID:21042276
Emerging roles for the non-canonical IKKs in cancer. 		KEEP AS NON CORE
Summary: Canonical NF-kappaB signal transduction (TAS). Records TBK1's NF-kappaB-pathway involvement; the positive-regulation term is the more informative capture.
Reason: Correct pathway context; subsumed by the positive-regulation-of-canonical-NF-kappaB annotation.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA
GO:0009615 response to virus
TAS
PMID:21042276
Emerging roles for the non-canonical IKKs in cancer. 		KEEP AS NON CORE
Summary: Response to virus: a generic parent of TBK1's specific antiviral/innate-immune role.
Reason: Correct but generic; the specific antiviral-innate-immune-response and type-I-IFN-production terms capture the core function more precisely.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0032481 positive regulation of type I interferon production
TAS
PMID:21042276
Emerging roles for the non-canonical IKKs in cancer. 		ACCEPT
Summary: Positive regulation of type I interferon production: core process by which TBK1 phosphorylates IRF3/IRF7 to induce IFN-alpha/IFN-beta.
Reason: Core biological process; TBK1 drives type I IFN induction via IRF3/IRF7 phosphorylation.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0045087 innate immune response
TAS
PMID:21042276
Emerging roles for the non-canonical IKKs in cancer. 		ACCEPT
Summary: Innate immune response: core biological process for TBK1.
Reason: Core biological process; TBK1 is central to innate immune signaling.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0032727 positive regulation of interferon-alpha production
IDA
PMID:16127453
IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I... 		ACCEPT
Summary: Positive regulation of interferon-alpha production: core output of TBK1/IRF7 activation in the RIG-I/MAVS (IPS-1) pathway.
Reason: Core biological process; TBK1 induces IFN-alpha via IRF activation.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB
GO:0032728 positive regulation of interferon-beta production
IDA
PMID:16127453
IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I... 		ACCEPT
Summary: Positive regulation of interferon-beta production: a specific, core output of TBK1-mediated IRF3 activation.
Reason: Core biological process; TBK1 induces IFN-beta via IRF3.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB
GO:0045944 positive regulation of transcription by RNA polymerase II
IDA
PMID:16127453
IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I... 		KEEP AS NON CORE
Summary: Positive regulation of transcription by RNA polymerase II: an indirect consequence of TBK1 activating IRF3/IRF7 transcription factors.
Reason: Indirect (via IRF activation); non-core. The IFN-production terms capture the relevant output.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
leading to transcriptional activation of pro-inflammatory and antiviral genes
GO:0005515 protein binding
IPI
PMID:19419966
The tyrosine kinase c-Src enhances RIG-I (retinoic acid-indu... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0005515 protein binding
IPI
PMID:20174559
Optineurin negatively regulates the induction of IFNbeta in ... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0051219 phosphoprotein binding
IPI
PMID:14530355
Toll/IL-1 receptor domain-containing adaptor inducing IFN-be... 		KEEP AS NON CORE
Summary: Phosphoprotein binding (TRIF/TICAM1 study). A specific interaction property; uninformative as a core function.
Reason: Records an interaction property; not a core function and subsumed by kinase activity.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
phosphorylating innate adapter proteins MAVS, STING1 and TICAM1
GO:0005829 cytosol
TAS
Reactome:R-HSA-1834939 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-3249378 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-918225 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-933527 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-937337 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9705010 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9705082 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9705137 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9705145 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9709831 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9709852 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9710988 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9754827 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9823910 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9823934 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9824888 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9828196 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9828209 		ACCEPT
Summary: Cytosolic localization from a Reactome reaction-step annotation. Correct core compartment, though one of many redundant per-step pathway localizations.
Reason: Correct cytosolic compartment where TBK1 signaling occurs; redundant with the experimental cytosol/cytoplasm evidence but consistent and retained as core.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005515 protein binding
IPI
PMID:16281057
SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- a... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0043123 positive regulation of canonical NF-kappaB signal transduction
IEP
PMID:12761501
Large-scale identification and characterization of human gen... 		ACCEPT
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.
Reason: Well-supported biological process; TBK1 was identified as an NF-kappaB-activating IKK-related kinase and phosphorylates RELA/NFKBIA/IKBKB under particular conditions.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
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
GO:0004672 protein kinase activity
NAS
PMID:10581243
NF-kappaB activation by a signaling complex containing TRAF2... 		ACCEPT
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.).
Reason: Core molecular function directly demonstrated by multiple experimental studies.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents
GO:0007249 canonical NF-kappaB signal transduction
TAS
PMID:10581243
NF-kappaB activation by a signaling complex containing TRAF2... 		KEEP AS NON CORE
Summary: Canonical NF-kappaB signal transduction (TAS). Records TBK1's NF-kappaB-pathway involvement; the positive-regulation term is the more informative capture.
Reason: Correct pathway context; subsumed by the positive-regulation-of-canonical-NF-kappaB annotation.
Supporting Evidence:
file:human/TBK1/TBK1-uniprot.txt
functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA

Core Functions

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:
protein serine/threonine kinase activity
Directly Involved In:
antiviral innate immune response positive regulation of type I interferon production
Cellular Locations:
cytosol
Supporting Evidence:
  • file:human/TBK1/TBK1-uniprot.txt
    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

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:
protein serine/threonine kinase activity
Directly Involved In:
positive regulation of macroautophagy positive regulation of xenophagy
Cellular Locations:
cytosol
Supporting Evidence:
  • file:human/TBK1/TBK1-uniprot.txt
    Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy

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:
protein serine/threonine kinase activity
Directly Involved In:
positive regulation of canonical NF-kappaB signal transduction
Cellular Locations:
cytosol
Supporting Evidence:
  • file:human/TBK1/TBK1-uniprot.txt
    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

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000116
Automatic Gene Ontology annotation based on Rhea mapping
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10581243
NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase.
PMID:10783893
NAK is an IkappaB kinase-activating kinase.
PMID:12761501
Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways.
PMID:14530355
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.
PMID:14703513
Identification of Ser-386 of interferon regulatory factor 3 as critical target for inducible phosphorylation that determines activation.
PMID:14743216
A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.
PMID:15367631
Activation of TBK1 and IKKvarepsilon kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunity.
PMID:15485837
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.
PMID:15841462
Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses.
PMID:16127453
IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction.
PMID:16281057
SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways.
PMID:16306936
Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response.
PMID:17142768
NAK-associated protein 1 participates in both the TLR3 and the cytoplasmic pathways in type I IFN induction.
PMID:17568778
SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK.
PMID:17599067
Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes.
PMID:18307994
Enhanced binding of TBK1 by an optineurin mutant that causes a familial form of primary open angle glaucoma.
PMID:18583960
The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response.
PMID:18636086
The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response.
PMID:18724357
STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling.
PMID:18818105
The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation.
PMID:19153231
Ebola virus protein VP35 impairs the function of interferon regulatory factor-activating kinases IKKepsilon and TBK-1.
PMID:19380580
Severe acute respiratory syndrome coronavirus M protein inhibits type I interferon production by impeding the formation of TRAF3.TANK.TBK1/IKKepsilon complex.
PMID:19416887
ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response.
PMID:19419966
The tyrosine kinase c-Src enhances RIG-I (retinoic acid-inducible gene I)-elicited antiviral signaling.
PMID:19433799
ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization.
PMID:20098747
Expanding the substantial interactome of NEMO using protein microarrays.
PMID:20174559
Optineurin negatively regulates the induction of IFNbeta in response to RNA virus infection.
PMID:20562859
Network organization of the human autophagy system.
PMID:20628368
Tom70 mediates activation of interferon regulatory factor 3 on mitochondria.
PMID:21042276
Emerging roles for the non-canonical IKKs in cancer.
PMID:21138416
Novel cross-talk within the IKK family controls innate immunity.
PMID:21270402
TANK-binding kinase 1 attenuates PTAP-dependent retroviral budding through targeting endosomal sorting complex required for transport-I.
PMID:21464307
IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation.
PMID:21617041
Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth.
PMID:21813773
IFN-induced TPR protein IFIT3 potentiates antiviral signaling by bridging MAVS and TBK1.
PMID:21903422
Mapping a dynamic innate immunity protein interaction network regulating type I interferon production.
PMID:21931555
Vaccinia virus protein C6 is a virulence factor that binds TBK-1 adaptor proteins and inhibits activation of IRF3 and IRF7.
PMID:21931631
Functional dissection of the TBK1 molecular network.
PMID:21988832
Toward an understanding of the protein interaction network of the human liver.
PMID:22000020
Activation of STAT6 by STING is critical for antiviral innate immunity.
PMID:22394562
STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway.
PMID:22412986
Activation of interferon regulatory factor 5 by site specific phosphorylation.
PMID:22921120
TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation.
PMID:22939624
Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition.
PMID:23096996
Hepatitis C virus NS2 protease inhibits host cell antiviral response by inhibiting IKKε and TBK1 functions.
PMID:23414517
A human skeletal muscle interactome centered on proteins involved in muscular dystrophies: LGMD interactome.
PMID:23542348
Hepatitis C virus NS4B blocks the interaction of STING and TBK1 to evade host innate immunity.
PMID:24056301
The deubiquitylase USP33 discriminates between RALB functions in autophagy and innate immune response.
PMID:24509444
Suppression of innate antiviral response by severe acute respiratory syndrome coronavirus M protein is mediated through the first transmembrane domain.
PMID:24560620
NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING.
PMID:24622840
SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex.
PMID:24643253
MAVS protein is attenuated by rotavirus nonstructural protein 1.
PMID:24696485
Murine gammaherpesvirus 68 encoding open reading frame 11 targets TANK binding kinase 1 to negatively regulate the host type I interferon response.
PMID:24807708
RIOK3 is an adaptor protein required for IRF3-mediated antiviral type I interferon production.
PMID:25636800
Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation.
PMID:25736436
WDFY1 mediates TLR3/4 signaling by recruiting TRIF.
PMID:25803835
Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia.
PMID:27035970
Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria.
PMID:27086836
The TBK1-binding domain of optineurin promotes type I interferon responses.
PMID:27094905
Middle East respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3.
PMID:27103069
Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death.
PMID:27135603
A TRAF-like motif of the inducible costimulator ICOS controls development of germinal center TFH cells via the kinase TBK1.
PMID:28011935
TTLL12 Inhibits the Activation of Cellular Antiviral Signaling through Interaction with VISA/MAVS.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:28747347
TRIM8 Negatively Regulates TLR3/4-Mediated Innate Immune Response by Blocking TRIF-TBK1 Interaction.
PMID:28871090
TRIM23 mediates virus-induced autophagy via activation of TBK1.
PMID:29150432
The IKK-related kinase TBK1 activates mTORC1 directly in response to growth factors and innate immune agonists.
PMID:29251827
Quantitative Proteomics Identified TTC4 as a TBK1 Interactor and a Positive Regulator of SeV-Induced Innate Immunity.
PMID:29441066
TANK-Binding Kinase 1 (TBK1) Isoforms Negatively Regulate Type I Interferon Induction by Inhibiting TBK1-IRF3 Interaction and IRF3 Phosphorylation.
PMID:30354798
Ccdc61 controls centrosomal localization of Cep170 and is required for spindle assembly and symmetry.
PMID:30561431
A protein-protein interaction map of the TNF-induced NF-κB signal transduction pathway.
PMID:31390091
TRAF3IP3 mediates the recruitment of TRAF3 to MAVS for antiviral innate immunity.
PMID:31530866
TBK1 Limits mTORC1 by Promoting Phosphorylation of Raptor Ser877.
PMID:31662325
Phosphorylation of RAB7 by TBK1/IKKε Regulates Innate Immune Signaling in Triple-Negative Breast Cancer.
PMID:31709703
TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls autophagosome shedding by ATG4 protease.
PMID:32209697
Noncanonical STAT1 phosphorylation expands its transcriptional activity into promoting LPS-induced IL-6 and IL-12p40 production.
PMID:32298923
E3 ubiquitin ligase ASB8 negatively regulates interferon via regulating TBK1/IKKi homeostasis.
PMID:32353859
A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.
PMID:32707033
Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.
PMID:32979938
Evasion of Type I Interferon by SARS-CoV-2.
PMID:33060197
Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.
PMID:33372174
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.
PMID:33707416
SARS-CoV-2 non-structural protein 13 (nsp13) hijacks host deubiquitinase USP13 and counteracts host antiviral immune response.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:34084167
SARS-CoV-2 Membrane Protein Inhibits Type I Interferon Production Through Ubiquitin-Mediated Degradation of TBK1.
PMID:34166398
SARS-CoV-2 viral proteins NSP1 and NSP13 inhibit interferon activation through distinct mechanisms.
PMID:34524948
Global Proximity Interactome of the Human Macroautophagy Pathway.
PMID:37219487
Large-scale phosphomimetic screening identifies phospho-modulated motif-based protein interactions.
PMID:37403426
MicroRNA-4691-3p inhibits the inflammatory response by targeting STING in human dental pulp cells: A laboratory investigation.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
Reactome:R-HSA-1606327
Phosphorylation and release of IRF3
Reactome:R-HSA-166245
Phosphorylation of IRF-3/IRF7 and their release from the activated TLR complex
Reactome:R-HSA-166271
IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR4
Reactome:R-HSA-1834939
STING recruits TBK1 and IRF3
Reactome:R-HSA-1834941
STING mediated induction of host immune responses
Reactome:R-HSA-2396002
TBK1 is phosphorylated within STING:TBK1:IRF3 complex
Reactome:R-HSA-2396007
IRF3 is phosphorylated by TBK1
Reactome:R-HSA-3249371
TBK1 phosphorylates STAT6 at Ser407
Reactome:R-HSA-3249378
STING recruits TBK1 and STAT6
Reactome:R-HSA-3249386
DTX4 ubiquitinates p-S172-TBK1 within NLRP4:DTX4:dsDNA:ZBP1:TBK1
Reactome:R-HSA-3249390
TBK1 is phosphorylated within STING:TBK1:STAT6 complex
Reactome:R-HSA-3249392
NLRP4 and DTX4 associate with p-S172-TBK1 within STING:TBK1:IRF3
Reactome:R-HSA-3270619
IRF3-mediated induction of type I IFN
Reactome:R-HSA-5205685
PINK1-PRKN Mediated Mitophagy
Reactome:R-HSA-8948703
NLRP4 and DTX4 associate with p-S172-TBK1 within dsDNA:ZBP1:TBK1
Reactome:R-HSA-8948709
DTX4 ubiquitinates p-S172-TBK1 within NLRP4:DTX4:STING:TBK1:IRF3
Reactome:R-HSA-9008684
TBK1 phosphorylation
Reactome:R-HSA-9013978
Phosphorylation of IRF-3/IRF7 and their release from the activated TLR3 complex
Reactome:R-HSA-9013979
IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR3
Reactome:R-HSA-918225
TBK1/IKK epsilon complex interacts with MAVS bound TRAF3
Reactome:R-HSA-918229
Phosphorylation and release of IRF3/IRF7
Reactome:R-HSA-918232
Recruitment of IRF3,IRF7
Reactome:R-HSA-933525
Phosphorylation and release of IRF7
Reactome:R-HSA-933527
Recruitment of TBK1/IKK epsilon complex to TANK:TRAF6
Reactome:R-HSA-933538
Recruitment of IRF7 to TRAF6
Reactome:R-HSA-937337
TAX1BP1:A20 inhibit TBK1/IKKi K63-polyubiquitination
Reactome:R-HSA-9679819
TBK1 binds amlexanox
Reactome:R-HSA-9705010
SARS-CoV-2 nsp6 binds TBK1
Reactome:R-HSA-9705082
SARS-CoV-2 nsp13 binds TBK1
Reactome:R-HSA-9705137
TBK1 or IKBKE forms homodimers
Reactome:R-HSA-9705145
TBK1, IKBKE form homodimers
Reactome:R-HSA-9705320
TBK1, IKBKE are autophosphorylated at Ser172
Reactome:R-HSA-9705323
Phosphorylation of TBK1/IKBKE
Reactome:R-HSA-9709831
HSP90 binds TBK1 and IRF3
Reactome:R-HSA-9709852
MAVS:TOMM70 recruits HSP90:TBK1:IRF3
Reactome:R-HSA-9710988
SARS-CoV-1 M protein interacts with TBK1/IKBKE
Reactome:R-HSA-9754827
SARS-CoV-2 M binds TBK1
Reactome:R-HSA-9817397
TBK1, IKBKE phosphorylate RIPK1 at T189
Reactome:R-HSA-9817411
TBK1, IKBKE binds Met1-polyUb within the TNFR1 complex
Reactome:R-HSA-9823904
TBK1 is ubiquitinated within TBK1:K63polyUb-TANK:K63polyUb-TRAF3:TRIF:activated TLR4
Reactome:R-HSA-9823906
TBK1 is phosphorylated within the activated TLR4 complex
Reactome:R-HSA-9823910
Recruitment of TBK1 to K63polyUb-TANK:K63polyUb-TRAF3:TRIF:activated TLR4
Reactome:R-HSA-9823934
OPTN binds TBK1 within the activated TLR4 complex
Reactome:R-HSA-9824888
OPTN, TBK1 bind ubiquitinated MOM proteins
Reactome:R-HSA-9824892
MAP1LC3B binds p-S-OPTN bound to Ub-mitochondria
Reactome:R-HSA-9824894
TBK1 is phosphorylated within TBK1:OPTN:Ub-mitochondrial proteins
Reactome:R-HSA-9824897
p-S-TBK1 phosphorylates OPTN
Reactome:R-HSA-9828196
TBK1 binds K63-pUb-TANK:K63-pUb-TRAF3:TRIF:activated TLR3
Reactome:R-HSA-9828200
TBK1 is ubiquitinated within TBK1:K63polyUb-TANK:K63polyUb-TRAF3:TRIF:activated TLR3
Reactome:R-HSA-9828205
TBK1 is phosphorylated within the activated TLR3 complex
Reactome:R-HSA-9828209
OPTN binds TBK1 within the activated TLR3 complex
Reactome:R-HSA-9840807
OPTN binds ATG9A

Suggested Questions for Experts

Q: 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?

Q: 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

Experiment: 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.

Experiment: 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.

Deep Research

Falcon

(TBK1-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 36 citations 3 artifacts 2026-06-14T16:18:56.586384
Edison artifact artifact-00 (text/markdown)
Edison artifact artifact-01 (text/markdown)
## Context ID: pqac-00000015 I have extracted the requested panels from Figure 2 and the corresponding figure legend. - **Immunofluorescence panels (B, C, E, F) (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Human TBK1 (TANK-binding kinase 1; UniProt Q9UHD2)

0) Target verification (critical)

The evidence reviewed here consistently refers to human TANK-binding kinase 1 (TBK1), a serine/threonine protein kinase in the IKK-related kinase family, activated by dimerization/oligomerization and Ser172 (S172) trans-autophosphorylation, and functioning downstream of STING/MAVS innate-immune signalosomes and in selective autophagy/mitophagy via cargo receptors such as OPTN and NDP52—matching the UniProt identity Q9UHD2. (miranda2024emergingrolesof pages 3-4, yamano2024optineurinprovidesa pages 12-13, hu2024mechanismoftbk1 pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 What TBK1 is

TBK1 is an enzyme (EC 2.7.11.1) that catalyzes protein phosphorylation on Ser/Thr residues, acting as a signal-transduction node that converts innate-immune receptor engagement into transcriptional programs (type I interferons; inflammatory genes) and also modulates membrane-trafficking and autophagy-related processes. (miranda2024emergingrolesof pages 3-4, yamano2024optineurinprovidesa pages 12-13)

1.2 Canonical pathway definition: nucleic-acid sensing → TBK1 → IRFs

A core, widely used definition of TBK1’s canonical role is: cytosolic nucleic-acid sensors (e.g., RNA-sensing via MAVS, DNA-sensing via cGAS–STING) recruit and activate TBK1, which then phosphorylates IRF3 and IRF7, enabling type I interferon induction. (miranda2024emergingrolesof pages 3-4, yamano2024optineurinprovidesa pages 12-13)

1.3 Key activation concepts

S172 phosphorylation is repeatedly described as the central biochemical “switch” for TBK1 catalytic activation and is promoted by dimer/oligomer formation and trans-autophosphorylation within TBK1 assemblies. (hu2024mechanismoftbk1 pages 2-3, miranda2024emergingrolesof pages 3-4, yamano2024optineurinprovidesa pages 12-13)

Recruitment to particular signaling complexes (via adaptor proteins such as TANK, NAP1/AZI2, and SINTBAD/TBKBP1) is emphasized as a major determinant of TBK1 substrate selection and localization, beyond what the kinase domain alone could specify in the cytosol. (miranda2024emergingrolesof pages 3-4, hu2024mechanismoftbk1 pages 1-2, paul2023thenoncanonicalfunction pages 17-20)

2) Molecular function: substrates, reaction logic, and pathway positioning

2.1 Substrate spectrum and pathway outputs

Innate immunity (STING/MAVS pathways). TBK1 is recruited to STING signalosomes after STING activation/oligomerization on post-Golgi membranes and then drives downstream phosphorylation events including IRF3/IRF7 activation to induce IFN-I programs, with additional coupling into NF-κB outputs in multiple contexts. (miranda2024emergingrolesof pages 3-4, yamano2024optineurinprovidesa pages 12-13)

Selective autophagy/mitophagy. TBK1 also functions as a selective-autophagy kinase: when recruited to ubiquitinated cargo, it phosphorylates autophagy receptors—particularly OPTN and NDP52 (CALCOCO2)—thereby increasing their effective interactions with ubiquitin and ATG8/LC3 proteins and promoting autophagosome biogenesis and cargo clearance. (paul2023thenoncanonicalfunction pages 15-17, yamano2024optineurinprovidesa pages 12-13, paul2023thenoncanonicalfunction pages 17-20)

2.2 Mechanism of TBK1 action in mitophagy (detailed, 2023–2024 emphasis)

A major 2024 mechanistic advance is the demonstration that OPTN provides a physical “contact site” for TBK1 activation during PINK1/Parkin-dependent mitophagy, assembling an OPTN–TBK1 complex at mitochondria–autophagosome formation interfaces and generating a positive-feedback loop: OPTN promotes TBK1 activation, and activated TBK1 promotes OPTN function. (yamano2024optineurinprovidesa pages 1-2)

This work highlights S172 autophosphorylation as the activation switch and reports that TBK1 deletion prevents OPTN localization to autophagosome formation sites, while OPTN deletion blocks TBK1 autophosphorylation, strongly supporting reciprocal dependency in mitophagy initiation. (yamano2024optineurinprovidesa pages 1-2)

At the level of phosphorylation sites relevant to mechanism, OPTN phosphorylation sites discussed include S177 (in/near LIR) and S473 (in UBAN), which are linked to OPTN’s improved association with ubiquitin-coated mitochondria and trafficking to autophagosome formation sites. (yamano2024optineurinprovidesa pages 12-13)

2.3 A newly defined innate-immune-to-cytoskeleton axis (2024): TBK1 → Zyxin

A 2024 EMBO Journal study identifies a STING/MAVS–TBK1 signaling axis that reaches the actin adhesion machinery via Zyxin. In this model, nucleic-acid sensing activates TBK1, resulting in robust phosphorylation of Zyxin at S142/S143, with phospho-Zyxin colocalizing with TBK1 puncta and subsequently localizing to focal adhesions to modulate F-actin organization and macrophage motility. (zhou2024tbk1zyxinsignalingcontrols pages 4-5)

The same study reports that TBK1 inhibitors BX795 or MRT67307 eliminate Zyxin phosphorylation, paralleling their suppression of IRF3 phosphorylation, supporting Zyxin as a TBK1-dependent downstream output of innate-immune activation (directly or indirectly). (zhou2024tbk1zyxinsignalingcontrols pages 4-5)

Figure evidence. The immunofluorescence and immunoblot panels extracted from this work show pZyxin colocalization with TBK1 puncta and focal adhesions and quantify phosphorylation changes during innate-immune stimulation and inhibitor treatment. (zhou2024tbk1zyxinsignalingcontrols media 698b1cfa)

3) Regulation and activation mechanisms (latest research emphasized)

3.1 Core activation by oligomerization and S172 autophosphorylation

Recent reviews consolidate a model in which TBK1 becomes catalytically competent when brought into higher-order assemblies, undergoing trans-autophosphorylation at S172; this is strongly tied to innate-immune signalosome formation (e.g., STING oligomers) and to cargo-receptor scaffolding in selective autophagy. (miranda2024emergingrolesof pages 3-4, yamano2024optineurinprovidesa pages 12-13)

A 2024 review focused on cancer contexts further emphasizes that S172 phosphorylation is tightly linked to TBK1 catalytic activation and notes upstream inputs capable of triggering or amplifying S172 phosphorylation (including pathways involving ULK1, PKCθ, and RalB/Sec5-dependent recruitment). (hu2024mechanismoftbk1 pages 2-3, hu2024mechanismoftbk1 pages 1-2)

3.2 PTK2B (PYK2) as an upstream activator via TBK1 Tyr591 (2023)

A 2023 Nature Communications study provides evidence for a specific activating tyrosine phosphorylation event: PTK2B directly phosphorylates TBK1 at Tyr591 (Y591), located in TBK1’s scaffolding/dimerization region, which enhances TBK1 activation by increasing oligomerization. (lin2023ptk2bpromotestbk1 pages 9-10)

The same work reports that PTK2B also promotes STING oligomerization, via a kinase-independent mechanism, providing a coherent explanation for how PTK2B can amplify STING–TBK1 signaling from multiple angles. (lin2023ptk2bpromotestbk1 pages 9-10)

4) Subcellular localization: where TBK1 acts

TBK1’s function is tightly linked to its recruitment to distinct subcellular “platforms”:

  • Post-Golgi STING signalosomes/aggregates: STING oligomerization on post-Golgi membranes recruits TBK1 and supports TBK1 trans-autophosphorylation and downstream IRF signaling. (yamano2024optineurinprovidesa pages 12-13)
  • Mitochondria–autophagosome formation contact sites during mitophagy: OPTN-dependent assembly of OPTN–TBK1 complexes at these interfaces supports TBK1 activation and autophagosome biogenesis on damaged mitochondria. (yamano2024optineurinprovidesa pages 1-2)
  • TBK1 puncta and focal adhesions in innate-immune-to-adhesion remodeling: pZyxin (S142/S143) is observed colocalized with TBK1 puncta and then at focal adhesions upon innate immune stimulation. (zhou2024tbk1zyxinsignalingcontrols pages 4-5, zhou2024tbk1zyxinsignalingcontrols media 698b1cfa)

5) Recent developments and latest research (prioritizing 2023–2024)

Key 2023–2024 developments with strong experimental support in this corpus include:

  1. Mitophagy activation platform model (OPTN–TBK1): OPTN provides a scaffold for TBK1 activation at mitochondria–autophagosome contact sites, establishing reciprocal positive feedback in mitophagy initiation (EMBO J, Feb 2024). URL: https://doi.org/10.1038/s44318-024-00036-1 (yamano2024optineurinprovidesa pages 1-2)
  2. PTK2B→TBK1 Y591 activation mechanism: PTK2B phosphorylates TBK1 at Y591 to enhance oligomerization/activation, and independently supports STING oligomerization (Nat Commun, Nov 2023). URL: https://doi.org/10.1038/s41467-023-43419-4 (lin2023ptk2bpromotestbk1 pages 9-10)
  3. STING/MAVS–TBK1–Zyxin axis: TBK1-driven phosphorylation of Zyxin at S142/S143 links innate immune sensing to focal adhesion/F-actin remodeling and macrophage migration (EMBO J, Sep 2024). URL: https://doi.org/10.1038/s44318-024-00244-9 (zhou2024tbk1zyxinsignalingcontrols pages 4-5, zhou2024tbk1zyxinsignalingcontrols media 698b1cfa)
  4. Cancer-centered synthesis of upstream TBK1 activation: review literature consolidates growth-factor and oncogenic pathways (e.g., KRAS→RalB/Sec5; PKCθ-linked complexes) that activate TBK1 through S172-centric mechanisms (Cell Insight, Oct 2024). URL: https://doi.org/10.1016/j.cellin.2024.100197 (hu2024mechanismoftbk1 pages 2-3, hu2024mechanismoftbk1 pages 1-2)

6) Current applications and real-world implementations

6.1 TBK1 as a therapeutic target/modulator in viral immunopathology (COVID-19)

A 2023 Nature Communications study proposes that dampening TBK1/IKKε signaling can blunt maladaptive inflammatory programs in SARS-CoV-2 infection. The authors report a preliminary Phase I study in which rectal delivery of idronoxil (IDX) was well-tolerated in 38 hospitalized patients with moderate COVID-19, and they cite an excellent safety profile in humans established in >600 cancer patients. URL: https://doi.org/10.1038/s41467-023-41381-9 (Sep 2023). (ullah2023pharmacologicalinhibitionof pages 7-8)

In a Vero-cell SARS-CoV-2 infection assay described in the methods, the virus was used at MOI 0.002, and IDX was tested using 3-fold serial dilutions starting at 50 μM (Remdesivir starting at 20 μM), illustrating a concrete translational screening setup. (ullah2023pharmacologicalinhibitionof pages 7-8)

6.2 TBK1 inhibition in neuroinflammatory pain models (preclinical)

A 2024 Cell Communication and Signaling study of painful diabetic neuropathy (PDN) reports TBK1 activation in the spinal dorsal horn and uses TBK1-siRNA and the TBK1 inhibitor amlexanox (AMX) as interventions; the study’s statistical plan reports sample size n=5 per group based on repeated behavioral measures power calculations (α=0.05, power=0.8). URL: https://doi.org/10.1186/s12964-024-01723-6 (Jul 2024). (liao2024targetingtankbindingkinase pages 4-5)

6.3 TBK1 genetics for diagnosis/stratification in FTD (patient-facing implementation)

A 2024 Alzheimer’s Research & Therapy study of a Chinese FTD cohort (n=261) identifies TBK1 variants in 7 individuals, and reports a pooled Chinese-cohort TBK1 mutation frequency of 2.0% (95% CI 1.0%–3.1%) in a meta-analysis, positioning TBK1 among the most frequent genetic contributors to FTD in that population. URL: https://doi.org/10.1186/s13195-024-01493-w (Jun 2024). (nan2024geneticandclinical pages 1-3, nan2024geneticandclinical pages 18-20)

This work also links patient variants to mechanistic function: TBK1 I37T and E232Q show reduced TBK1 autophosphorylation, and I37T reduces OPTN phosphorylation, while E696G increases OPTN–TBK1 complex formation, directly connecting TBK1 disease variants to altered kinase activation and selective-autophagy signaling. (nan2024geneticandclinical pages 1-3, nan2024geneticandclinical pages 18-20)

7) Expert synthesis and analysis (authoritative sources)

A 2024 Trends in Cancer review frames TBK1 as a context-dependent regulator that integrates innate immune sensing (STING/MAVS/TLR inputs) with broader outputs including NF-κB signaling and autophagy, arguing that adaptor-driven recruitment (TANK/SINTBAD/AZI2) is critical for TBK1’s diverse functions and that TBK1 has multiple roles in tumor–immune interactions beyond tumor-intrinsic survival signaling. URL: https://doi.org/10.1016/j.trecan.2024.02.007 (Mar 2024). (miranda2024emergingrolesof pages 3-4)

A 2024 focused review on TBK1 activation in cancer emphasizes that upstream kinase inputs and scaffolding complexes likely initiate and amplify S172 phosphorylation and that autophagy can also impose negative feedback by degrading activated TBK1, highlighting TBK1 as a dynamically regulated signaling hub rather than a simple on/off kinase. URL: https://doi.org/10.1016/j.cellin.2024.100197 (Oct 2024). (hu2024mechanismoftbk1 pages 2-3)

8) Disease associations (database-supported overview)

Open Targets disease–target association evidence links TBK1 to multiple conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia and/or ALS 4, as well as COVID-19 and certain autoinflammatory/infectious phenotypes, reflecting the combined genetic and mechanistic literature around TBK1’s roles in neurodegeneration and innate immunity. (OpenTargets Search: -TBK1)

9) Summary tables and figure evidence

The following tables summarize TBK1 functional annotation and translational evidence:

Functional area Key concepts/definition Core molecular mechanism Key substrates/partners Subcellular localization Representative 2023-2024 sources (with DOI URLs)
Innate immune signaling (STING/MAVS→TBK1→IRF3/7) TBK1 is a human serine/threonine kinase and central effector of nucleic-acid sensing that couples STING or MAVS signalosomes to type I interferon output; activation requires dimerization/oligomerization and Ser172 trans-autophosphorylation (miranda2024emergingrolesof pages 3-4, yamano2024optineurinprovidesa pages 12-13, hu2024mechanismoftbk1 pages 1-2) STING oligomerization on post-Golgi membranes recruits TBK1 dimers, enabling trans-autophosphorylation at S172 and phosphorylation of IRF3/IRF7; MAVS/TLR pathways likewise recruit TBK1 through adaptors such as TANK, NAP1/AZI2, and SINTBAD/TBKBP1 to drive IFN and some NF-κB responses (miranda2024emergingrolesof pages 3-4, yamano2024optineurinprovidesa pages 12-13, hu2024mechanismoftbk1 pages 1-2, paul2023thenoncanonicalfunction pages 17-20) STING, MAVS, TANK, NAP1/AZI2, SINTBAD/TBKBP1, IRF3, IRF7; K63-linked ubiquitination at Lys30/Lys401 contributes to activation (miranda2024emergingrolesof pages 3-4, hu2024mechanismoftbk1 pages 1-2) Cytosol; ER-to-post-Golgi STING signalosomes; pathogen-sensing complexes (miranda2024emergingrolesof pages 3-4, yamano2024optineurinprovidesa pages 12-13) Miranda et al., 2024, Trends Cancer, https://doi.org/10.1016/j.trecan.2024.02.007; Lin et al., 2023, Nat Commun, https://doi.org/10.1038/s41467-023-43419-4; Wegner et al., 2023, Front Immunol, https://doi.org/10.3389/fimmu.2023.1073608 (miranda2024emergingrolesof pages 3-4, lin2023ptk2bpromotestbk1 pages 9-10)
Autophagy/mitophagy TBK1 is a selective-autophagy/mitophagy kinase that amplifies ubiquitin-driven recruitment of cargo receptors and early autophagosome machinery; OPTN can act as a platform for TBK1 activation at mitophagy contact sites (yamano2024optineurinprovidesa pages 1-2, yamano2024optineurinprovidesa pages 12-13, paul2023thenoncanonicalfunction pages 17-20) Upon mitochondrial damage or ubiquitinated cargo accumulation, TBK1 is recruited by OPTN/NDP52/TAX1BP1-containing assemblies; TBK1 autophosphorylation activates phosphorylation of mitophagy receptors, increasing their binding to ubiquitin, ATG8 proteins, and FIP200, thereby promoting phagophore assembly and cargo clearance (paul2023thenoncanonicalfunction pages 15-17, yamano2024optineurinprovidesa pages 1-2, yamano2024optineurinprovidesa pages 12-13, paul2023thenoncanonicalfunction pages 17-20) OPTN, NDP52/CALCOCO2, TAX1BP1, FIP200, LC3/ATG8 family, ATG9A, RAB7A; OPTN sites include S177 and S473 in the LIR/UBAN region (yamano2024optineurinprovidesa pages 1-2, yamano2024optineurinprovidesa pages 12-13, paul2023thenoncanonicalfunction pages 17-20) Damaged mitochondria; mitochondria–autophagosome formation contact sites; ubiquitin-coated bacteria/cargo; lysosome-associated autophagy initiation complexes (yamano2024optineurinprovidesa pages 1-2, yamano2024optineurinprovidesa pages 12-13, paul2023thenoncanonicalfunction pages 17-20) Yamano et al., 2024, EMBO J, https://doi.org/10.1038/s44318-024-00036-1; Nguyen et al., 2023, Mol Cell/bioRxiv record, https://doi.org/10.1101/2022.08.14.503930; Schmid et al., 2024, Front Immunol, https://doi.org/10.3389/fimmu.2024.1356369 (yamano2024optineurinprovidesa pages 1-2, yamano2024optineurinprovidesa pages 12-13)
Focal-adhesion / cytoskeletal signaling Recent work identifies TBK1 as a regulator of actin-adhesion remodeling through Zyxin, linking innate immune sensing to cell motility and tissue positioning (zhou2024tbk1zyxinsignalingcontrols pages 4-5, zhou2024tbk1zyxinsignalingcontrols media 698b1cfa) STING or MAVS signalosomes activate TBK1, which drives Zyxin phosphorylation at S142/S143; phospho-Zyxin colocalizes with TBK1 puncta and focal adhesions, promoting focal-adhesion/F-actin reorganization and reducing macrophage migration (zhou2024tbk1zyxinsignalingcontrols pages 4-5, zhou2024tbk1zyxinsignalingcontrols media 698b1cfa) Zyxin; upstream STING/MAVS signalosomes; downstream F-actin/focal-adhesion machinery; TBK1 inhibitors BX795 and MRT67307 suppress Zyxin phosphorylation together with IRF3 phosphorylation (zhou2024tbk1zyxinsignalingcontrols pages 4-5, zhou2024tbk1zyxinsignalingcontrols media 698b1cfa) STING aggregates/signalosomes, TBK1 puncta, focal adhesions, macrophage cytoplasm (zhou2024tbk1zyxinsignalingcontrols pages 4-5, zhou2024tbk1zyxinsignalingcontrols media 698b1cfa) Zhou et al., 2024, EMBO J, https://doi.org/10.1038/s44318-024-00244-9 (zhou2024tbk1zyxinsignalingcontrols pages 4-5, zhou2024tbk1zyxinsignalingcontrols media 698b1cfa)
Upstream activation by PTK2B PTK2B/PYK2 is an upstream tyrosine kinase that enhances TBK1 activation in antiviral signaling by promoting TBK1 oligomerization (lin2023ptk2bpromotestbk1 pages 9-10) PTK2B directly phosphorylates TBK1 at Tyr591 in the scaffold/dimerization domain, increasing TBK1 oligomerization and activation; PTK2B also promotes STING oligomerization through a kinase-independent mechanism, strengthening STING–TBK1 signaling (lin2023ptk2bpromotestbk1 pages 9-10) PTK2B, TBK1 Y591, STING, IRF3; PTK2B deficiency reduces antiviral signaling and increases susceptibility to viral infection in mouse models (lin2023ptk2bpromotestbk1 pages 9-10) Golgi-associated granules/signalosomes containing STING and TBK1 during infection; immune-cell cytoplasm (lin2023ptk2bpromotestbk1 pages 9-10) Lin et al., 2023, Nat Commun, https://doi.org/10.1038/s41467-023-43419-4 (lin2023ptk2bpromotestbk1 pages 9-10)
Cancer context TBK1 is frequently positioned as a multifunctional cancer-cell survival and tumor-immune regulator, especially in KRAS-driven and inflammatory tumor contexts; its effects can be tumor-promoting or context-dependent via IFN-I pathways (hu2024mechanismoftbk1 pages 2-3, miranda2024emergingrolesof pages 3-4, hu2024mechanismoftbk1 pages 1-2) Oncogenic inputs such as KRAS→RalB/Sec5 and growth-factor→TBK1–TBKBP1–CARD10–PKCθ pathways increase TBK1 activation (including S172 and S716-linked regulation), supporting NF-κB/IFN signaling, anti-apoptotic transcription, autophagy, and tumor–microenvironment crosstalk (hu2024mechanismoftbk1 pages 2-3, hu2024mechanismoftbk1 pages 1-2) RalB, Sec5, PKCθ, TBKBP1, CARD10, NEMO, IRF3, NF-κB components including c-Rel and BCL-xL-linked outputs; additional reported substrates include Sec5, p62, and OPTN (hu2024mechanismoftbk1 pages 2-3, miranda2024emergingrolesof pages 3-4) Cytosol and signalosome-associated compartments; Golgi-associated pre-autophagosome initiation sites; tumor and immune-cell compartments (hu2024mechanismoftbk1 pages 2-3, miranda2024emergingrolesof pages 3-4) Hu & Zhang, 2024, Cell Insight, https://doi.org/10.1016/j.cellin.2024.100197; Miranda et al., 2024, Trends Cancer, https://doi.org/10.1016/j.trecan.2024.02.007; Wang et al., 2024, Front Immunol, https://doi.org/10.3389/fimmu.2024.1433321 (hu2024mechanismoftbk1 pages 2-3, miranda2024emergingrolesof pages 3-4)

Table: This table summarizes the major functional areas of human TBK1 (UniProt Q9UHD2), including its core mechanisms, substrates, localization, and recent representative sources. It is useful as a compact reference for innate immunity, autophagy, cytoskeletal signaling, upstream activation, and cancer-related roles.

Use case/disease area Compound/inhibitor or intervention Mechanism (TBK1/IKKε etc) Model/system Key quantitative/statistical details Notes/limitations Source (with DOI URL and date)
COVID-19 / SARS-CoV-2 hyper-inflammation Idronoxil (IDX) Small-molecule inhibitor that suppresses TBK1/IKKε signaling by destabilizing TBK1/IKKε protein complexes; proposed to limit harmful inflammatory signaling rather than directly target viral replication (ullah2023pharmacologicalinhibitionof pages 7-8, ullah2023pharmacologicalinhibitionof pages 8-9) Murine SARS-CoV-2 immunopathology model; supporting cell-based assays including Vero infection assay and multiple innate-immune reporter/cell systems (ullah2023pharmacologicalinhibitionof pages 7-8, ullah2023pharmacologicalinhibitionof pages 8-9) Preliminary Phase I rectal-delivery study reported good tolerability in 38 hospitalized moderate COVID-19 patients; human safety profile cited as established in >600 cancer patients; antiviral assay used MOI 0.002, with IDX tested in 3-fold serial dilution from 50 μM (Remdesivir from 20 μM) (ullah2023pharmacologicalinhibitionof pages 7-8) Quantitative efficacy values are not provided in the extracted text; translational rationale is stronger than direct clinical efficacy evidence here; effects may reflect broader TBK1/IKKε pathway modulation (ullah2023pharmacologicalinhibitionof pages 7-8, ullah2023pharmacologicalinhibitionof pages 8-9) Ullah et al., Nature Communications, 2023-09, https://doi.org/10.1038/s41467-023-41381-9 (ullah2023pharmacologicalinhibitionof pages 7-8, ullah2023pharmacologicalinhibitionof pages 8-9)
Innate immune / cytoskeletal signaling; tumor immunity MRT67307 Pharmacologic TBK1 inhibitor used to block TBK1 kinase activity; in this context suppresses Zyxin phosphorylation downstream of STING/MAVS-TBK1 signaling (zhou2024tbk1zyxinsignalingcontrols pages 4-5, zhou2024tbk1zyxinsignalingcontrols media 698b1cfa) Primary macrophages and cell systems stimulated by HSV-1, SeV, poly(I:C), diABZI, or cGAMP; focal-adhesion/TBK1 puncta imaging and immunoblot analyses (zhou2024tbk1zyxinsignalingcontrols pages 4-5, zhou2024tbk1zyxinsignalingcontrols media 698b1cfa) Immunofluorescence quantification used n = 4 per group for panel E and n = 3 per group for panel F; inhibitor treatment eliminated inducible pZyxin(S142/S143) in parallel with loss of pIRF3, while not eliminating TBK1 S172 phosphorylation signal in the reported assays (zhou2024tbk1zyxinsignalingcontrols pages 4-5) Primarily a mechanistic research tool, not a clinically validated TBK1 therapy; extracted text does not provide dose-response or in vivo human data (zhou2024tbk1zyxinsignalingcontrols pages 4-5, zhou2024tbk1zyxinsignalingcontrols media 698b1cfa) Zhou et al., The EMBO Journal, 2024-09, https://doi.org/10.1038/s44318-024-00244-9 (zhou2024tbk1zyxinsignalingcontrols pages 4-5, zhou2024tbk1zyxinsignalingcontrols media 698b1cfa)
Innate immune / cytoskeletal signaling; tumor immunity BX795 TBK1 inhibitor used experimentally to abrogate TBK1 activity and downstream Zyxin phosphorylation in STING/MAVS-TBK1-Zyxin pathway studies (zhou2024tbk1zyxinsignalingcontrols pages 4-5, zhou2024tbk1zyxinsignalingcontrols media 698b1cfa) Same macrophage and cell-signaling systems as above; nucleic-acid sensing and focal-adhesion remodeling assays (zhou2024tbk1zyxinsignalingcontrols pages 4-5, zhou2024tbk1zyxinsignalingcontrols media 698b1cfa) Inhibiting TBK1 with BX795 or MRT67307 eliminated Zyxin phosphorylation, paralleling inhibition of IRF3 phosphorylation during HSV-1/SeV/poly(I:C) responses; figure-based quantification used n = 3-4 independent experiments depending on panel (zhou2024tbk1zyxinsignalingcontrols pages 4-5) Widely used but known in the field as a multi-kinase tool compound; extracted text here focuses on mechanistic inference, not therapeutic translation (zhou2024tbk1zyxinsignalingcontrols pages 4-5, zhou2024tbk1zyxinsignalingcontrols media 698b1cfa) Zhou et al., The EMBO Journal, 2024-09, https://doi.org/10.1038/s44318-024-00244-9 (zhou2024tbk1zyxinsignalingcontrols pages 4-5, zhou2024tbk1zyxinsignalingcontrols media 698b1cfa)
Painful diabetic neuropathy (PDN) Amlexanox (AMX) TBK1 inhibitor proposed to reduce microglial pyroptosis and noncanonical NF-κB/NLRP3-linked inflammatory signaling in PDN (paper describes it as a TBK1 inhibitor) (liao2024targetingtankbindingkinase pages 4-5) Mouse PDN models including streptozotocin-induced T1DM and db/db T2DM-related neuropathy; spinal dorsal horn/microglial analyses plus behavioral and nerve-injury readouts (liao2024targetingtankbindingkinase pages 4-5) Power calculation used α = 0.05, power = 0.8, and sample size = 5/group for repeated behavioral measures; intrathecal TBK1 siRNA 10 μg/mouse and Ac-YVAD-cmk 10 nmol/mouse were used in intervention experiments; systemic AMX was reported to improve peripheral nerve injury (liao2024targetingtankbindingkinase pages 4-5) The extracted pages do not provide a specific AMX dose or effect size; evidence is preclinical and includes siRNA plus inhibitor data rather than a standalone drug-development package (liao2024targetingtankbindingkinase pages 4-5) Liao et al., Cell Communication and Signaling, 2024-07, https://doi.org/10.1186/s12964-024-01723-6 (liao2024targetingtankbindingkinase pages 4-5)
Frontotemporal dementia (FTD) genetics / patient stratification TBK1 variant screening and functional characterization Human genetic association plus functional assays of TBK1 variants affecting autophosphorylation and OPTN-related autophagy signaling (nan2024geneticandclinical pages 1-3, nan2024geneticandclinical pages 18-20, nan2024geneticandclinical pages 20-22) Chinese FTD cohort and meta-analysis; in vitro HEK293T functional assays for TBK1 mutants and OPTN phosphorylation/complex formation (nan2024geneticandclinical pages 1-3, nan2024geneticandclinical pages 18-20, nan2024geneticandclinical pages 20-22) In the cohort, 61/261 (23.4%) carried potential causative FTD-gene variants; TBK1 variants were found in 7 patients; pooled Chinese FTD meta-analysis estimated TBK1 mutation frequency at 2.0% (95% CI 1.0%-3.1%); one excerpt also reports 19/751 positive cases overall; functional assays showed I37T and E232Q had decreased TBK1 autophosphorylation, and I37T reduced OPTN phosphorylation, while E696G increased OPTN-TBK1 complex formation (nan2024geneticandclinical pages 1-3, nan2024geneticandclinical pages 18-20, nan2024geneticandclinical pages 20-22) Translational value is strongest for diagnosis/genetic stratification rather than immediate drug intervention; some cohort/count discrepancies across excerpts likely reflect different filtering definitions (all variants vs pathogenic subsets) and should be interpreted carefully (nan2024geneticandclinical pages 1-3, nan2024geneticandclinical pages 18-20, nan2024geneticandclinical pages 20-22, nan2024geneticandclinical pages 4-6) Nan et al., Alzheimer's Research & Therapy, 2024-06, https://doi.org/10.1186/s13195-024-01493-w (nan2024geneticandclinical pages 1-3, nan2024geneticandclinical pages 18-20, nan2024geneticandclinical pages 20-22, nan2024geneticandclinical pages 4-6)

Table: This table summarizes translationally relevant TBK1 evidence across infection, inflammation, neuropathy, and neurodegenerative genetics. It highlights compounds, mechanisms, models, and quantitative details that are useful for prioritizing TBK1-related therapeutic or biomarker opportunities.

A representative figure extraction supporting the STING/MAVS–TBK1–Zyxin axis and TBK1 inhibitor effects is shown here: (zhou2024tbk1zyxinsignalingcontrols media 698b1cfa)

10) Limitations of this report (evidence constraints)

Some frequently discussed TBK1 topics (e.g., comprehensive kinase kinetic constants, full inhibitor selectivity panels, and broad clinical-trial landscapes specific to TBK1 inhibitors) were not available in the extracted full-text segments retrieved in this run; accordingly, quantitative pharmacology is reported only where explicitly present in the accessible text. (ullah2023pharmacologicalinhibitionof pages 7-8, liao2024targetingtankbindingkinase pages 4-5)

References

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Artifacts

Citations

  1. yamano2024optineurinprovidesa pages 1-2
  2. yamano2024optineurinprovidesa pages 12-13
  3. ullah2023pharmacologicalinhibitionof pages 7-8
  4. liao2024targetingtankbindingkinase pages 4-5
  5. miranda2024emergingrolesof pages 3-4
  6. paul2023thenoncanonicalfunction pages 17-20
  7. paul2023thenoncanonicalfunction pages 15-17
  8. nan2024geneticandclinical pages 1-3
  9. nan2024geneticandclinical pages 18-20
  10. ullah2023pharmacologicalinhibitionof pages 8-9
  11. nan2024geneticandclinical pages 20-22
  12. nan2024geneticandclinical pages 4-6
  13. https://doi.org/10.1038/s44318-024-00036-1
  14. https://doi.org/10.1038/s41467-023-43419-4
  15. https://doi.org/10.1038/s44318-024-00244-9
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  17. https://doi.org/10.1038/s41467-023-41381-9
  18. https://doi.org/10.1186/s12964-024-01723-6
  19. https://doi.org/10.1186/s13195-024-01493-w
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  22. https://doi.org/10.1038/s41467-023-43419-4;
  23. https://doi.org/10.3389/fimmu.2023.1073608
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  25. https://doi.org/10.1101/2022.08.14.503930;
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📚 Additional Documentation

Notes

(TBK1-notes.md)

TBK1 (TANK-binding kinase 1) review notes

UniProt Q9UHD2, 729 aa. Non-canonical IKK-related serine/threonine kinase. Domain architecture:
N-terminal protein kinase domain, a ubiquitin-like domain (ULD), a scaffold/dimerization domain,
and a C-terminal coiled-coil region mediating homodimerization
[file:human/TBK1/TBK1-uniprot.txt "and a C-terminal coiled-coil region mediating homodimerization"].
Cytoplasmic [file:human/TBK1/TBK1-uniprot.txt "SUBCELLULAR LOCATION: Cytoplasm"]. Activated by
trans-autophosphorylation at Ser172. Ubiquitous, higher in testis.

Core molecular function: protein Ser/Thr kinase

Extensively documented IDA/EXP protein serine/threonine kinase activity (GO:0004674, GO:0106310,
GO:0004672). [file:human/TBK1/TBK1-uniprot.txt "Serine/threonine kinase that plays an essential
role in regulating inflammatory responses to foreign agents"]. ATP binding (GO:0005524) is part of
the catalytic mechanism. This is the unambiguous core MF — ACCEPT all kinase-activity and ATP-binding
annotations (collapse redundant evidence; the EXP/IDA ones are the strongest).

Core BP 1: innate antiviral immunity / type I IFN induction

TBK1 phosphorylates the innate adaptor proteins MAVS, STING1 (TMEM173), and TICAM1/TRIF on their
pLxIS motif, recruiting and then phosphorylating IRF3 (and IRF7), driving IFN-alpha/IFN-beta
[file:human/TBK1/TBK1-uniprot.txt "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"]. PMID:25636800. PMID:14703513 Ser-386 of IRF3 (IDA kinase activity +
antiviral innate immune response + positive regulation of type I IFN production). PMID:22394562
STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA pathway. cGAS/STING signaling
(GO:0140896, TAS). Core: ACCEPT antiviral innate immune response (GO:0140374), positive regulation
of type I IFN production (GO:0032481), positive regulation of IFN-alpha/IFN-beta production
(GO:0032727/GO:0032728), activation of innate immune response (GO:0002218), cGAS/STING pathway.

Core BP 2: selective autophagy / mitophagy / xenophagy via autophagy-receptor phosphorylation

TBK1 phosphorylates OPTN/optineurin on Ser177, enhancing LC3 binding and antibacterial autophagy
PMID:21617041.
PMID:27035970 — mitophagy via OPTN/NDP52/TAX1BP1/SQSTM1.
TBK1 phosphorylates SMCR8 (C9orf72-SMCR8 complex) promoting autophagosome maturation
[file:human/TBK1/TBK1-uniprot.txt "Phosphorylates SMCR8 component of the C9orf72-SMCR8 complex,
promoting autophagosome maturation"]. Phosphorylates ATG8s MAP1LC3C and GABARAPL2 to prevent
delipidation PMID:31709703. PMID:22921120 autophagy-mediated antimicrobial defense / autophagosome
maturation. PMID:28871090 TRIM23-mediated virus-induced autophagy via TBK1. Core: ACCEPT
positive regulation of macroautophagy (GO:0016239), positive regulation of autophagy (GO:0010508),
positive regulation of xenophagy (GO:1904417), macroautophagy (GO:0016236).

Core BP 3: NF-kappaB activation (the original "TANK-binding kinase")

Original identification as IKK-related kinase activating NF-kappaB via a TRAF2-TANK-TBK1 complex
PMID:10581243. PMID:10783893. Under particular
conditions TBK1 phosphorylates NFKBIA, IKBKB, or RELA. PMID:12761501 IEP positive regulation of
canonical NF-kappaB. canonical NF-kappaB signal transduction (GO:0007249, TAS). These are real
but more context-specific than the dominant IRF3/IFN and autophagy axes; treat NF-kappaB BP terms as
ACCEPT (well-established) or KEEP_AS_NON_CORE for the most generic.

Secondary / pleiotropic roles -> KEEP_AS_NON_CORE

  • mTOR signaling: activates mTORC1 in response to growth factors (GO:1904263 pos reg TORC1,
    PMID:29150432) but also limits mTORC1 via RPTOR Ser877 (GO:1904262 neg reg TORC1, PMID:31530866);
    positive regulation of TORC2 (GO:1904515, ISS/IEA); positive regulation of TOR signaling
    (GO:0032008, IEA). Context-dependent, pleiotropic -> KEEP_AS_NON_CORE.
  • AKT1 phosphorylation (PMID:21464307) -> reflected in kinase activity EXP annotation.
  • T follicular helper cell differentiation (GO:0061470, PMID:27135603) -> developmental/pleiotropic,
    KEEP_AS_NON_CORE.
  • TLR4 signaling (GO:0034142, PMID:28747347), TLR-pathway -> KEEP_AS_NON_CORE (upstream context).
  • inflammatory response (GO:0006954), response to virus (GO:0009615), defense response (GO:0006952),
    response to other organism (GO:0051707) -> generic parents, KEEP_AS_NON_CORE.
  • positive regulation of transcription by RNA Pol II (GO:0045944, PMID:16127453) -> indirect
    (via IRF activation), KEEP_AS_NON_CORE.
  • peptidyl-serine/threonine phosphorylation (GO:0018105/GO:0018107), protein phosphorylation
    (GO:0006468) -> generic MF-process parents of the specific substrate phosphorylations,
    KEEP_AS_NON_CORE.
  • RAB7 phosphorylation in TNBC (PMID:31662325) -> kinase activity EXP.
  • regulation of RIPK1-mediated cell death (RIPK1 T189, Reactome) -> not a standalone GOA BP here.

Localization

Cytoplasm/cytosol is the core compartment (many EXP/IDA/IBA/TAS). ACCEPT cytoplasm/cytosol
is_active_in/located_in (collapse the dozens of redundant Reactome cytosol located_in to
KEEP_AS_NON_CORE as generic pathway-step localizations, but they are correct).
GO:0005654 nucleoplasm (IDA, GO_REF:0000052 immunofluorescence/HPA) — a minor pool; TBK1 is
predominantly cytoplasmic and acts there. KEEP_AS_NON_CORE.

protein binding / interaction annotations

Dozens of IPI GO:0005515 "protein binding" annotations record interactions with adaptors (TANK,
AZI2/NAP1, SINTBAD/TBKBP1, OPTN, STING, MAVS, TRAF3, DDX3X, SIKE, IFIT3, RIOK3, etc.), regulators,
and numerous viral antagonists (HCV NS2/NS3/NS4B, SARS-CoV/CoV-2 M/nsp6/nsp13, MERS M, Ebola VP35,
vaccinia C6, rotavirus NSP1, gammaherpesvirus ORF11, etc.). Functionally important but bare
protein binding is uninformative -> KEEP_AS_NON_CORE for all GO:0005515.

Specific informative interaction MFs:
- GO:0061629 RNA Pol II transcription factor binding (PMID:22412986, IRF5) -> KEEP_AS_NON_CORE
(records substrate/IRF binding; the kinase activity is the core).
- GO:0051219 phosphoprotein binding (PMID:14530355) -> KEEP_AS_NON_CORE.
- GO:0019903 protein phosphatase binding (IEA/ISS) -> KEEP_AS_NON_CORE.
- GO:0042802 identical protein binding (IEA, homodimerization) -> KEEP_AS_NON_CORE (real homodimer
but uninformative term; the coiled-coil mediates homodimerization).

REMOVE candidates (clearly-wrong electronic over-propagations)

  • GO:0003676 nucleic acid binding (IEA, GO_REF:0000107 Ensembl ortholog): TBK1 is a protein kinase;
    there is no evidence it is a sequence-nonspecific nucleic-acid-binding protein. This looks like an
    erroneous orthology-based electronic transfer. MARK_AS_OVER_ANNOTATED (or REMOVE) — choose
    MARK_AS_OVER_ANNOTATED to be conservative since it is electronic, not experimental.
  • GO:0010629 negative regulation of gene expression (IEA, GO_REF:0000107 ortholog): overly generic,
    not the documented TBK1 role (TBK1 positively drives IFN/antiviral gene expression). Electronic
    ortholog transfer -> MARK_AS_OVER_ANNOTATED.

Both are IEA (no experimental basis) so safe to flag; not experimental annotations.

Disease relevance (context for description, not GO actions)

Familial ALS/FTD (haploinsufficiency, PMID:25803835), normal-tension/POAG glaucoma (GLC1P, OPTN
axis, PMID:18307994), herpes simplex encephalopathy (IIAE8), autoinflammation (AIARV). These
underscore the autophagy/innate-immunity core functions.

Pn Notes

(TBK1-pn-notes.md)

TBK1 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9UHD2
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-14
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • 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/core annotation action counts: ACCEPT: 129; KEEP_AS_NON_CORE: 87; MARK_AS_OVER_ANNOTATED: 2

PN Consistency Summary

  • Consistency: TBK1 is correctly framed in PN notes and review as the catalytic kinase that phosphorylates receptors (OPTN-Ser177, p62, NDP52, TAX1BP1), not as a receptor itself. Review/notes (Wild 2011, Richter/Heo 2016 PMID:27035970) match. The PN dossier itself flags the mTORC1-modulator and UBL-domain-kinase nodes as no_mapping/context (no over-propagation) — internally consistent.
  • PN story / NEW pressure: PN's lone projected term is GO:0000423 mitophagy (process), marked more_specific_than_existing_goa. This is a mismatch with how TBK1 actually acts: TBK1 regulates mitophagy by phosphorylating receptors. GOA and the review correctly use regulatory terms — GO:0016239 positive regulation of macroautophagy (ACCEPT), GO:1904417 positive regulation of xenophagy, GO:0010508 positive regulation of autophagy. Annotating bare GO:0000423 mitophagy (involved_in) to the kinase risks the same over-reach the project warns against; positive-regulation-of-mitophagy framing is more defensible.
  • Evidence alignment: Strong overlap (SMCR8 review, TBK1-autophagy review, Richter 2016 PNAS mitophagy, PINK1 receptor recruitment). Same papers underlie review's positive-regulation terms.
  • Verdict: CONSISTENT on biology; PN's bare GO:0000423 mitophagy projection is scope drift for a regulator — review's positive-regulation terms are better. Recommended edits: [MAP] for TBK1 the "Autophagy receptor regulation|Mitophagy" node should project a regulation term (GO:1901526 positive regulation of mitophagy, verified real) rather than the bare process GO:0000423; do not add GO:0000423 involved_in to the kinase review.

Full Consistency Review

  • UniProt: Q9UHD2 (TANK-binding kinase 1) · batch: proteostasis-batch-2026-06-14 · review status: COMPLETE (~3069 lines; ~55 IPI bare-protein-binding non-core)
  • PN placement: ALP Pre-initiation autophagy signaling|mTORC1 pathway, direct|Modulator of mTORC1 activity + Autophagy substrate selection|Autophagy receptor regulation|Mitophagy + UPS Ubiquitin and UBL proteins|UBL domain|other enzymes|kinase ; PN-node mapping: Receptor-regulation/Mitophagy→GO:0000423 (more_specific_than_existing_goa); mTORC1-modulator type no_mapping (class context_only GO:0010506 regulation of autophagy); UBL-domain ancestors context_only; ancestors no_mapping.
  • Consistency: TBK1 is correctly framed in PN notes and review as the catalytic kinase that phosphorylates receptors (OPTN-Ser177, p62, NDP52, TAX1BP1), not as a receptor itself. Review/notes (Wild 2011, Richter/Heo 2016 PMID:27035970) match. The PN dossier itself flags the mTORC1-modulator and UBL-domain-kinase nodes as no_mapping/context (no over-propagation) — internally consistent.
  • PN story / NEW pressure: PN's lone projected term is GO:0000423 mitophagy (process), marked more_specific_than_existing_goa. This is a mismatch with how TBK1 actually acts: TBK1 regulates mitophagy by phosphorylating receptors. GOA and the review correctly use regulatory terms — GO:0016239 positive regulation of macroautophagy (ACCEPT), GO:1904417 positive regulation of xenophagy, GO:0010508 positive regulation of autophagy. Annotating bare GO:0000423 mitophagy (involved_in) to the kinase risks the same over-reach the project warns against; positive-regulation-of-mitophagy framing is more defensible.
  • Mapping strategy: PN node is "Autophagy receptor regulation" yet the projected GO term is the bare process GO:0000423, not a regulation term — internal scope drift. The narrower/regulatory review terms are preferable (TOMM20 precedent: prefer the more accurate term over the broader projected process). KEY PATTERN: TBK1 = kinase, so cargo-adaptor MF does not apply; core MF is GO:0004674 Ser/Thr kinase (ACCEPT).
  • Evidence alignment: Strong overlap (SMCR8 review, TBK1-autophagy review, Richter 2016 PNAS mitophagy, PINK1 receptor recruitment). Same papers underlie review's positive-regulation terms.
  • Verdict: CONSISTENT on biology; PN's bare GO:0000423 mitophagy projection is scope drift for a regulator — review's positive-regulation terms are better. Recommended edits: [MAP] for TBK1 the "Autophagy receptor regulation|Mitophagy" node should project a regulation term (GO:1901526 positive regulation of mitophagy, verified real) rather than the bare process GO:0000423; do not add GO:0000423 involved_in to the kinase review.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-14
  • review_yaml: genes/human/TBK1/TBK1-ai-review.yaml
  • PN workbook rows: 3

PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, direct | Modulator of mTORC1 activity

  • UniProt: Q9UHD2
  • In branches: ALP, UPS
  • Notes: Enhances GTP exchange by SMCR8 by phosphorylation. Can activate or inhibit mTORC1 by phosphorylating MTOR or RPTOR, respectively. Also phosphorylates autophagy receptors Optinuerin (OPTN), NDP52, TAX1BP1, and P62 when bound to TANK, linking ubiquitinated cargo to autophagic membranes. Constitutive interaction of TBK1 with OPTN and OPTN binding with ubiquitin chains are essential for TBK1 recruitment and kinase activation on mitochondria.
  • PN references (titles):
    • Full article: Multifaceted role of SMCR8 as autophagy regulator (tandfonline.com)
    • TBK1 (TANK-binding kinase 1)-mediated regulation of autophagy in health and disease - ScienceDirect
    • Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria | PNAS
    • Expanding the ubiquitin code through post-translational modification
    • The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy
  • PN-node mapping records (path + ancestors):
    • [type] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, direct|Modulator of mTORC1 activity
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
    • [group] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, direct
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
    • [class] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling
      status=context_only scope=too_broad_to_propagate GO=[GO:0010506 regulation of autophagy]
      rationale: This class organizes upstream signaling inputs to autophagy initiation. Because the subtree contains generic insulin, AMPK, mTORC1, nutrient-sensing, and miscellaneous signaling components, class-level propagation to regulation of autophagy would over-annotate many genes.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Autophagy-Lysosome Pathway | Autophagy substrate selection | Autophagy receptor regulation | Mitophagy

  • UniProt: Q9UHD2
  • In branches: ALP, UPS
  • Notes: Enhances GTP exchange by SMCR8 by phosphorylation. Can activate or inhibit mTORC1 by phosphorylating MTOR or RPTOR, respectively. Also phosphorylates autophagy receptors Optinuerin (OPTN), NDP52, TAX1BP1, and P62 when bound to TANK, linking ubiquitinated cargo to autophagic membranes. Constitutive interaction of TBK1 with OPTN and OPTN binding with ubiquitin chains are essential for TBK1 recruitment and kinase activation on mitochondria.
  • PN references (titles):
    • Full article: Multifaceted role of SMCR8 as autophagy regulator (tandfonline.com)
    • TBK1 (TANK-binding kinase 1)-mediated regulation of autophagy in health and disease - ScienceDirect
    • Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria | PNAS
    • Expanding the ubiquitin code through post-translational modification
    • The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy
  • PN-node mapping records (path + ancestors):
    • [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Autophagy receptor regulation|Mitophagy
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0000423 mitophagy]
      rationale: The PN receptor-regulation type for mitophagy captures factors that tune receptor activity within the mitophagy pathway. This supports propagation to mitophagy while preserving that the source is a regulatory sub-role.
    • [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Autophagy receptor regulation
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
    • [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 3: Ubiquitin Proteasome System | Ubiquitin and UBL proteins | UBL domain | other enzymes | kinase

  • UniProt: Q9UHD2
  • In branches: ALP, UPS
  • Signature domains: IPR041087
  • Auxiliary domains: IPR000719
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL proteins|UBL domain|other enzymes|kinase
      status=no_mapping scope= GO=[]
      rationale: Reviewed manually as a UPS source node. No single GO term is appropriate for direct propagation from this PN label without narrower context or gene-level evidence.
    • [type] Ubiquitin Proteasome System|Ubiquitin and UBL proteins|UBL domain|other enzymes
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
    • [group] Ubiquitin Proteasome System|Ubiquitin and UBL proteins|UBL domain
      status=context_only scope=too_broad_to_propagate GO=[GO:0043130 ubiquitin binding]
      rationale: This group records UBL-domain protein context, but descendants include enzymes, adaptors, chaperone-related proteins, non-enzymatic proteins, and nucleic-acid factors. Propagation is restricted to narrower nodes.
    • [class] Ubiquitin Proteasome System|Ubiquitin and UBL proteins
      status=context_only scope=too_broad_to_propagate GO=[GO:0019787 ubiquitin-like protein transferase activity]
      rationale: This class groups ubiquitin, UBL modifiers, UBX/UBL-domain proteins, and UBL-containing enzymes. The branch is UPS-relevant but too mixed to propagate as a single GO annotation.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

  • GO:0000423 mitophagy | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Autophagy receptor regulation|Mitophagy

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
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.