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.