# 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 "Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation"]. [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 "The protein kinase TANK binding kinase 1 (TBK1) phosphorylated optineurin on serine-177, enhancing LC3 binding affinity and autophagic clearance of cytosolic Salmonella"]. [PMID:27035970 "Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria"] — 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 "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"]. 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.