id: Q92844
gene_symbol: TANK
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  TANK (TRAF family member-associated NF-kappa-B activator; also known as I-TRAF)
  is a cytoplasmic adaptor/scaffold protein, lacking any catalytic activity, that
  organizes signaling complexes in the innate immune and NF-kappaB pathways. It was
  first identified as a TRAF-interacting protein that binds the TRAF-C domains of
  TRAF1, TRAF2 and TRAF3 and modulates TRAF-mediated signaling. Its best-established
  role is as one of three mutually exclusive adaptors (alongside SINTBAD/TBKBP1 and
  NAP1/AZI2) that constitutively bind the IKK-related kinases TBK1 and IKBKE (IKKepsilon)
  via a central TBK1-binding domain and bridge them into complexes that phosphorylate
  IRF3/IRF7, driving type I interferon production during antiviral innate immunity;
  TBK1 activation in response to virus or poly(I:C) depends on the TANK-TBK1 interaction.
  TANK is the non-catalytic subunit of the TBK1-IKKepsilon-TANK kinase complex.
  TANK also has a separable negative-regulatory function: in response to genotoxic
  stress or interleukin-1/LPS it scaffolds a deubiquitination complex containing
  ZC3H12A (MCPIP1) and the deubiquitinase USP10, promoting USP10-dependent
  deubiquitination of TRAF6 (and NEMO/IKBKG) and thereby restraining canonical
  NF-kappaB activation. TANK itself contains no deubiquitinase domain, so its activity
  in this complex is purely as an assembly scaffold. Phosphorylation of TANK by IKBKE
  disrupts its binding to TRAF2, providing a phospho-switch on its adaptor function.
  Structurally TANK contains an N-terminal coiled-coil, a TBK1/IKBKE-binding region,
  a TRAF-interaction motif (which engages the CD40-recognition site of TRAF3), and a
  C-terminal UBZ1-type zinc finger. TANK is targeted by viral proteases (encephalomyocarditis
  virus and Seneca Valley virus 3C proteases cleave it; vaccinia C6 binds it) as an
  immune-evasion strategy, underscoring its role in the antiviral interferon response.
alternative_products:
- name: Long
  id: Q92844-1
- name: Short
  id: Q92844-2
  sequence_note: VSP_004442, VSP_004443
- name: '3'
  id: Q92844-3
  sequence_note: VSP_043702, VSP_043703
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location. TANK is a cytoplasmic adaptor, so this is correct and matches the experimental IDA cytoplasm annotation.
    action: ACCEPT
    reason: Correct core compartment; TANK acts as a cytoplasmic adaptor, consistent with the experimental IDA cytoplasm/cytosol annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0043124
    label: negative regulation of canonical NF-kappaB signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic assignment of negative regulation of canonical NF-kappaB signaling. This is corroborated by the experimental IMP of the same term (PMID:25861989) where TANK scaffolds USP10-dependent TRAF6 deubiquitination to restrain NF-kappaB.
    action: KEEP_AS_NON_CORE
    reason: Correct and supported by experimental evidence, but reflects the secondary genotoxic/IL-1 NF-kappaB-restraining role rather than TANK's core TBK1/IKK adaptor function; redundant with the IMP annotation.
    supported_by:
    - reference_id: PMID:25861989
      supporting_text: TANK negatively regulates NF-kappaB activation by DNA damage via inhibiting ubiquitination of TRAF6
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12005438
  qualifier: enables
  review:
    summary: IPI interaction with TRAF3 from the crystal structure study of the TANK peptide bound to the CD40-recognition site of TRAF3. A real, functionally important interaction, but bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the real TANK-TRAF3 interaction (structurally defined), but bare protein binding is uninformative per curation guidelines; the informative adaptor function is captured by GO:0060090.
    supported_by:
    - reference_id: PMID:12005438
      supporting_text: TANK binds to the CD40 recognition site on TRAF3
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14743216
  qualifier: enables
  review:
    summary: IPI interactions (TRAF2, TRAF3, TBK1) from a TNF-alpha/NF-kappaB pathway interaction map. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real pathway interactions (TRAF2/TRAF3/TBK1) but bare protein binding is uninformative; the adaptor function (GO:0060090) is the informative MF.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; Q12933: TRAF2; NbExp=10; IntAct=EBI-356349, EBI-355744'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17500595
  qualifier: enables
  review:
    summary: IPI interaction with HTT (huntingtin) from a genetic-modifier interactome screen. Bare protein binding is uninformative and this partner is not connected to TANK's core function.
    action: KEEP_AS_NON_CORE
    reason: Records a real but functionally peripheral interaction (HTT); bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; P42858: HTT; NbExp=3; IntAct=EBI-356349, EBI-466029'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17568778
  qualifier: enables
  review:
    summary: IPI interactions with IKBKE/IKKepsilon and TBK1 from the SINTBAD paper showing TANK shares a TBK1-binding domain with NAP1 and SINTBAD. A real, core-relevant interaction, but bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally central TANK-IKBKE/TBK1 interactions, but bare protein binding is uninformative; captured by the adaptor MF (GO:0060090).
    supported_by:
    - reference_id: PMID:17568778
      supporting_text: shares a TBK1-binding domain with NAP1 and TANK
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18307994
  qualifier: enables
  review:
    summary: IPI interaction with TBK1 reported in a study of an optineurin mutant enhancing TBK1 binding. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real TBK1 interaction but bare protein binding is uninformative; the adaptor function captures this.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; Q9UHD2: TBK1; NbExp=14; IntAct=EBI-356349, EBI-356402'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20562859
  qualifier: enables
  review:
    summary: IPI interaction (TRAF2) from a network analysis of the human autophagy system. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput network interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; Q12933: TRAF2; NbExp=10; IntAct=EBI-356349, EBI-355744'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21212807
  qualifier: enables
  review:
    summary: IPI interactions with SUMO1/SUMO2 from the study showing inducible SUMOylation of TANK alleviates its repression of TLR7 signaling. Bare protein binding is uninformative, but documents a regulatory SUMO modification of TANK.
    action: KEEP_AS_NON_CORE
    reason: Records real SUMO1/2 interactions (SUMOylation regulates TANK's repressor activity) but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; P63165: SUMO1; NbExp=8; IntAct=EBI-356349, EBI-80140'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21653829
  qualifier: enables
  review:
    summary: IPI interaction (TSC1) from an autism-disorder interactome study. Bare protein binding is uninformative and the partner is not core to TANK function.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; Q92574: TSC1; NbExp=3; IntAct=EBI-356349, EBI-1047085'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21903422
  qualifier: enables
  review:
    summary: IPI interactions (including TRAF2, TRAF3, TBK1) from a dynamic innate-immunity interaction network regulating type I interferon production. Bare protein binding is uninformative but the partners are core-relevant.
    action: KEEP_AS_NON_CORE
    reason: Records real innate-immune interactions but bare protein binding is uninformative; the type I IFN adaptor role is captured by GO:0032481/GO:0060090.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; Q9UHD2: TBK1; NbExp=14; IntAct=EBI-356349, EBI-356402'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21931555
  qualifier: enables
  review:
    summary: IPI interactions (vaccinia virus C6, IKBKE, TBK1) from the study showing vaccinia C6 binds TBK1 adaptor proteins to inhibit IRF3/IRF7. Bare protein binding is uninformative but supports TANK's role in the TBK1-IRF antiviral axis.
    action: KEEP_AS_NON_CORE
    reason: Records a host-virus interaction (C6) plus TBK1/IKBKE; bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:21931555
      supporting_text: binds TBK-1 adaptor proteins and inhibits activation of IRF3 and IRF7
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: IPI interactions from a human liver protein interaction network (includes PLK1, TRAF2, TRAF1, TBK1, NEMO). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; P53350: PLK1; NbExp=4; IntAct=EBI-356349, EBI-476768'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24008843
  qualifier: enables
  review:
    summary: IPI interaction with a viral protein (NS) from a structure-homology virus-host interaction study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Host-virus interaction predicted/validated by homology; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; P03495: NS; Xeno; NbExp=2; IntAct=EBI-356349, EBI-2548993'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: IPI interactions (SRSF11, TP53BP2, CEP63) from a proteome-scale human interactome map. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; Q05519: SRSF11; NbExp=3; IntAct=EBI-356349, EBI-1051785'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25852190
  qualifier: enables
  review:
    summary: IPI interaction (IKBKE) from a kinase-network analysis of TRAIL-induced apoptosis. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput kinase-network interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; Q14164: IKBKE; NbExp=5; IntAct=EBI-356349, EBI-307369'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26638075
  qualifier: enables
  review:
    summary: IPI interaction (CEP63) from a centrosome-cilium interface interactome. Bare protein binding is uninformative and peripheral to TANK function.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; Q96MT8: CEP63; NbExp=4; IntAct=EBI-356349, EBI-741977'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: IPI interaction (TRAF1) from a human interactome architecture study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; Q13077: TRAF1; NbExp=5; IntAct=EBI-356349, EBI-359224'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29251827
  qualifier: enables
  review:
    summary: IPI interaction with TBK1 from a quantitative proteomics study of the TBK1 interactome (TTC4 study). Bare protein binding is uninformative but the TBK1 partner is core-relevant.
    action: KEEP_AS_NON_CORE
    reason: Records the core TBK1 interaction but bare protein binding is uninformative; the adaptor function captures this.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; Q9UHD2: TBK1; NbExp=14; IntAct=EBI-356349, EBI-356402'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30561431
  qualifier: enables
  review:
    summary: IPI interactions (TRAF2, TRAF3, TBK1, NEMO/IKBKG) from a TNF-induced NF-kappaB pathway interaction map. Bare protein binding is uninformative but partners are pathway-relevant.
    action: KEEP_AS_NON_CORE
    reason: Records real NF-kappaB-pathway interactions but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; Q9Y6K9: IKBKG; NbExp=7; IntAct=EBI-356349, EBI-81279'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32707033
  qualifier: enables
  review:
    summary: IPI interaction (TBK1) from a kinase interaction network study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput kinase-network interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; Q9UHD2: TBK1; NbExp=14; IntAct=EBI-356349, EBI-356402'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: IPI interactions (TRAF1, TRAF2, TRAF3, TBK1, IKBKE, NEMO) from a cell-specific proteome-scale interactome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; Q13114: TRAF3; NbExp=8; IntAct=EBI-356349, EBI-357631'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34084167
  qualifier: enables
  review:
    summary: IPI interaction (TRAF3) from a study of SARS-CoV-2 M protein-mediated TBK1 degradation. Bare protein binding is uninformative but the host-virus innate-immune context is consistent with TANK's TBK1 axis role.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction in an innate-immune/host-virus context but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; Q13114: TRAF3; NbExp=8; IntAct=EBI-356349, EBI-357631'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: IPI interaction (NEMO/IKBKG) from a multimodal cell-map structural/functional genomics study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'Q92844; Q9Y6K9: IKBKG; NbExp=7; IntAct=EBI-356349, EBI-81279'
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence localization to the nucleolus. There is no functional literature placing TANK activity in the nucleolus; TANK is established as a cytoplasmic adaptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Derived from a single high-throughput immunofluorescence dataset (GO_REF:0000052) with no supporting functional evidence; conflicts with the consistently reported cytoplasmic localization and is likely an over-annotation/staining artifact.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence localization to the cytosol, consistent with TANK's established cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization (the compartment where TANK assembles TBK1/IKK and TRAF deubiquitination complexes); kept consistent with the other cytosol annotations. The core localization is captured by the IDA cytoplasm is_active_in annotation.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0051607
    label: defense response to virus
  evidence_type: NAS
  original_reference_id: PMID:21931631
  qualifier: involved_in
  review:
    summary: ComplexPortal author-statement assignment of antiviral defense for the TBK1-IKKepsilon-TANK complex. Consistent with TANK's role in the TBK1-IRF3/7 type I IFN antiviral axis.
    action: KEEP_AS_NON_CORE
    reason: Correct process-level role (downstream of TANK's adaptor function in the antiviral IFN response) but broad; the core is the TBK1 adaptor/type I IFN production function.
    supported_by:
    - reference_id: PMID:21931631
      supporting_text: TBK1 activation was strictly dependent on the integrity of the TBK1/TANK interaction
- term:
    id: GO:0060337
    label: type I interferon-mediated signaling pathway
  evidence_type: NAS
  original_reference_id: PMID:21931631
  qualifier: involved_in
  review:
    summary: ComplexPortal author-statement assignment of type I interferon-mediated signaling for the TBK1-IKKepsilon-TANK complex. Note this term denotes the response to interferon; TANK's documented role is in interferon induction/production rather than IFN-receptor signaling.
    action: KEEP_AS_NON_CORE
    reason: Process is closely related to TANK's antiviral IFN role; however GO:0060337 (the response to type I IFN) is less precise for TANK than GO:0032481 (positive regulation of type I interferon production), which is the experimentally supported core BP.
    supported_by:
    - reference_id: PMID:21931631
      supporting_text: TANK-binding kinase 1 (TBK1) and inducible IkappaB-kinase (IKK-i) are central regulators of type-I interferon induction
- term:
    id: GO:1902554
    label: serine/threonine protein kinase complex
  evidence_type: NAS
  original_reference_id: PMID:21931631
  qualifier: part_of
  review:
    summary: ComplexPortal assignment that TANK is part of the TBK1-IKKepsilon-TANK serine/threonine kinase complex (CPX-6089). TANK is the non-catalytic adaptor subunit of this kinase complex.
    action: ACCEPT
    reason: Core cellular component; TANK is a bona fide subunit of the TBK1/IKKepsilon kinase complex, which is the structural basis of its adaptor function.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: ComplexPortal; CPX-6089; TBK1-IKKepsilon-TANK complex.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:21931631
  qualifier: is_active_in
  review:
    summary: Direct evidence (immunofluorescence) that TANK is active in the cytoplasm, where it functions as a TBK1/IKKepsilon adaptor. Core localization.
    action: ACCEPT
    reason: Core localization with direct evidence; TANK acts as a cytoplasmic adaptor in the TBK1/IKK and TRAF-deubiquitination complexes.
    supported_by:
    - reference_id: PMID:21931631
      supporting_text: the individual adaptors reside in different subcellular locations
- term:
    id: GO:0032481
    label: positive regulation of type I interferon production
  evidence_type: IDA
  original_reference_id: PMID:21931631
  qualifier: involved_in
  review:
    summary: Direct evidence that TANK promotes type I interferon production via its TBK1 adaptor function; TBK1 activation in response to virus/poly(I:C) requires the TANK-TBK1 interaction. Core biological process.
    action: ACCEPT
    reason: Core biological process; TANK's TBK1-bridging adaptor function drives IRF3/IRF7-dependent type I IFN induction.
    supported_by:
    - reference_id: PMID:21931631
      supporting_text: TBK1 activation was strictly dependent on the integrity of the TBK1/TANK interaction
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:21931631
  qualifier: enables
  review:
    summary: Direct evidence that TANK functions as a molecular adaptor bridging TBK1/IKKepsilon into signaling complexes. This is TANK's defining core molecular function.
    action: ACCEPT
    reason: Core molecular function; TANK is a non-catalytic adaptor that links the IKK-related kinases (and TRAFs, and the USP10/ZC3H12A DUB complex) into functional assemblies.
    supported_by:
    - reference_id: PMID:21931631
      supporting_text: They are associated with three adaptor proteins called TANK, Sintbad ... and NAP1
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IMP
  original_reference_id: PMID:25861989
  qualifier: contributes_to
  review:
    summary: TANK lacks a deubiquitinase domain; the contributes_to qualifier reflects that TANK scaffolds the USP10-dependent deubiquitination of TRAF6, not that TANK itself has DUB activity. The catalytic DUB is USP10.
    action: KEEP_AS_NON_CORE
    reason: The contributes_to qualifier is acceptable for a non-catalytic scaffold that enables a complex DUB activity, but the activity resides in USP10; TANK's actual function here is better captured by molecular adaptor activity (GO:0060090) and deubiquitinase activator activity (GO:0035800).
    supported_by:
    - reference_id: PMID:25861989
      supporting_text: TANK formed a complex with MCPIP1 (also known as ZC3H12A) and a deubiquitinase, USP10, which was essential for the USP10-dependent deubiquitination of TRAF6
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IMP
  original_reference_id: PMID:25861989
  qualifier: involved_in
  review:
    summary: IMP evidence that TANK restrains genotoxic (DNA damage-induced) NF-kappaB activation via the USP10/ZC3H12A deubiquitination complex. A real but secondary process.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported but reflects the secondary genotoxic-stress NF-kappaB-restraining role; the term GO:0006974 is broad. The specific outcome (negative regulation of canonical NF-kappaB) is annotated separately.
    supported_by:
    - reference_id: PMID:25861989
      supporting_text: TANK negatively regulates NF-kappaB activation by DNA damage via inhibiting ubiquitination of TRAF6
- term:
    id: GO:0035800
    label: deubiquitinase activator activity
  evidence_type: IMP
  original_reference_id: PMID:25861989
  qualifier: enables
  review:
    summary: IMP evidence that TANK acts as a scaffold that activates/enables USP10-dependent deubiquitination of TRAF6. This is an informative molecular function for TANK's NF-kappaB-restraining scaffold role.
    action: KEEP_AS_NON_CORE
    reason: Real and informative MF (scaffold that activates a DUB), but reflects the secondary genotoxic/IL-1 NF-kappaB-restraining function rather than TANK's core TBK1 adaptor role.
    supported_by:
    - reference_id: PMID:25861989
      supporting_text: which was essential for the USP10-dependent deubiquitination of TRAF6 and the resolution of genotoxic NF-kappaB activation
- term:
    id: GO:0043124
    label: negative regulation of canonical NF-kappaB signal transduction
  evidence_type: IMP
  original_reference_id: PMID:25861989
  qualifier: involved_in
  review:
    summary: IMP evidence that TANK negatively regulates canonical NF-kappaB signaling; CRISPR deletion of TANK enhanced genotoxic NF-kappaB activation. This is the central outcome of TANK's scaffold role in TRAF6 deubiquitination.
    action: KEEP_AS_NON_CORE
    reason: Well-supported, important function, but it is a context-specific (genotoxic/IL-1) negative-feedback role distinct from TANK's core positive role as a TBK1/IKK adaptor in type I IFN induction. TANK is notable for this dual (positive in IFN, negative in NF-kappaB) behavior.
    supported_by:
    - reference_id: PMID:25861989
      supporting_text: CRISPR/Cas9-mediated deletion of TANK in human cells significantly enhanced NF-kappaB activation by genotoxic treatment
- term:
    id: GO:0071347
    label: cellular response to interleukin-1
  evidence_type: IMP
  original_reference_id: PMID:25861989
  qualifier: involved_in
  review:
    summary: IMP evidence that the TANK-MCPIP1-USP10 complex decreases TRAF6 ubiquitination in cells treated with IL-1beta, restraining the IL-1 NF-kappaB response.
    action: KEEP_AS_NON_CORE
    reason: Real but context-specific role (IL-1 signaling) downstream of TANK's deubiquitination-scaffold function; non-core.
    supported_by:
    - reference_id: PMID:25861989
      supporting_text: the TANK-MCPIP1-USP10 complex also decreased TRAF6 ubiquitination in cells treated with IL-1beta or LPS
- term:
    id: GO:0071356
    label: cellular response to tumor necrosis factor
  evidence_type: IMP
  original_reference_id: PMID:25861989
  qualifier: involved_in
  review:
    summary: IMP-supported involvement in TNF-related NF-kappaB responses, consistent with TANK's documented modulation of TRAF2/TNFR signaling. Context-specific, non-core.
    action: KEEP_AS_NON_CORE
    reason: Real but secondary cytokine-response role downstream of the NF-kappaB-restraining scaffold function; non-core.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: May control negatively TRAF2-mediated NF-kappa-B activation signaled by CD40, TNFR1 and TNFR2
- term:
    id: GO:0071479
    label: cellular response to ionizing radiation
  evidence_type: IMP
  original_reference_id: PMID:25861989
  qualifier: involved_in
  review:
    summary: IMP evidence linking TANK to the genotoxic-stress (ionizing radiation/DNA damage) NF-kappaB response via the USP10/TRAF6 deubiquitination axis.
    action: KEEP_AS_NON_CORE
    reason: Real but secondary genotoxic-stress role; non-core relative to TANK's TBK1 adaptor function.
    supported_by:
    - reference_id: PMID:25861989
      supporting_text: regulating cellular response to genotoxic stress
- term:
    id: GO:1903003
    label: positive regulation of protein deubiquitination
  evidence_type: IMP
  original_reference_id: PMID:25861989
  qualifier: involved_in
  review:
    summary: IMP evidence that TANK promotes USP10-mediated deubiquitination of TRAF6 (positive regulation of protein deubiquitination). Captures TANK's scaffold function in the DUB complex.
    action: KEEP_AS_NON_CORE
    reason: Accurate process annotation for the deubiquitination-scaffold role; non-core relative to the TBK1 adaptor function.
    supported_by:
    - reference_id: PMID:25861989
      supporting_text: USP10-dependent deubiquitination of TRAF6 and the resolution of genotoxic NF-κB
- term:
    id: GO:2000158
    label: positive regulation of ubiquitin-specific protease activity
  evidence_type: IMP
  original_reference_id: PMID:25861989
  qualifier: involved_in
  review:
    summary: IMP evidence that TANK positively regulates the activity of the ubiquitin-specific protease USP10 toward TRAF6 by scaffolding it into the deubiquitination complex.
    action: KEEP_AS_NON_CORE
    reason: Accurate process annotation for the USP10-scaffold role; non-core relative to TANK's TBK1 adaptor function.
    supported_by:
    - reference_id: PMID:25861989
      supporting_text: which was essential for the USP10-dependent deubiquitination of TRAF6
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25861989
  qualifier: enables
  review:
    summary: IPI interactions with USP10, ZC3H12A/MCPIP1, TRAF6 and NEMO/IKBKG from the genotoxic NF-kappaB study. Functionally central interactions, but bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the real components of the TANK deubiquitination complex, but bare protein binding is uninformative; the scaffold/adaptor function captures these.
    supported_by:
    - reference_id: PMID:25861989
      supporting_text: TANK formed a complex with MCPIP1 (also known as ZC3H12A) and a deubiquitinase, USP10
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:25861989
  qualifier: part_of
  review:
    summary: IDA evidence that TANK is part of a protein-containing complex (the TANK-MCPIP1/ZC3H12A-USP10 deubiquitination complex). Generic complex term.
    action: KEEP_AS_NON_CORE
    reason: Correct but maximally generic; the specific complex membership (TBK1-IKKepsilon-TANK kinase complex; TANK-USP10-ZC3H12A DUB complex) is captured by more informative annotations.
    supported_by:
    - reference_id: PMID:25861989
      supporting_text: TANK formed a complex with MCPIP1 (also known as ZC3H12A) and a deubiquitinase, USP10
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-166245
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-166271
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5362500
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9013978
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9013979
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9013990
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9823904
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9823906
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9823910
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9823932
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9823934
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9823939
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9824882
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9828196
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9828200
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9828204
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9828205
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9828209
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9830706
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9830710
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:11279055
  qualifier: enables
  review:
    summary: IPI interaction with a TRAF-domain ubiquitin ligase (TRAF family member) from a survey of TRAF-domain-containing proteins. More informative than bare protein binding (it specifies binding to a ubiquitin ligase), reflecting TANK's TRAF-interaction function.
    action: KEEP_AS_NON_CORE
    reason: Informative MF capturing TANK's binding to TRAF E3 ligases (its original I-TRAF function), but secondary to the TBK1/IKK adaptor core; retained as non-core.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: Also interacts with TRAF1, TRAF2, and TRAF3 by binding to their TRAF-C domains
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21784977
  qualifier: enables
  review:
    summary: IPI interaction (tristetraprolin/ZFP36, P26651) from a study of TTP/CCL3 mRNA and tissue inflammation. Bare protein binding is uninformative and peripheral to TANK's core function.
    action: KEEP_AS_NON_CORE
    reason: Records a real but peripheral interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBUNIT: Homodimer.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5362486
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9013985
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-933525
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-933527
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-933537
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-933538
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9705145
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9705323
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation placing TANK in the cytosol within TLR/TBK1-IKKepsilon-IRF3/7 activation reactions. Correct compartment, consistent with TANK's cytoplasmic adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic localization but derived from generic pathway-step context; redundant with the experimental IDA cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TANK/TANK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: TAS
  original_reference_id: PMID:8710854
  qualifier: involved_in
  review:
    summary: Author-statement (original I-TRAF paper) that TANK is involved in TRAF-mediated signal transduction. Maximally generic process term.
    action: KEEP_AS_NON_CORE
    reason: Correct but extremely generic; the specific NF-kappaB/type I IFN signaling roles are captured by more informative annotations.
    supported_by:
    - reference_id: PMID:8710854
      supporting_text: I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  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: PMID:11279055
  title: A diverse family of proteins containing tumor necrosis factor receptor-associated
    factor domains.
  findings: []
- id: PMID:12005438
  title: Downstream regulator TANK binds to the CD40 recognition site on TRAF3.
  findings:
  - statement: Crystal structure of a TANK peptide (174-194) bound to TRAF3 shows TANK engages the same CD40-recognition surface of the TRAF3 TRAF-C domain; point mutations (Q182A, T184A, D185A) abolish TANK binding to TRAF2/TRAF3.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Structural basis of the TANK-TRAF interaction (the original I-TRAF function). Supports the TRAF-binding annotations.
- id: PMID:14743216
  title: A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction
    pathway.
  findings: []
- id: PMID:17500595
  title: Huntingtin interacting proteins are genetic modifiers of neurodegeneration.
  findings: []
- id: PMID:17568778
  title: SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding
    domain with NAP1 and TANK.
  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:20562859
  title: Network organization of the human autophagy system.
  findings: []
- id: PMID:21212807
  title: Inducible SUMO modification of TANK alleviates its repression of TLR7 signalling.
  findings: []
- id: PMID:21653829
  title: Protein interactome reveals converging molecular pathways among autism disorders.
  findings: []
- id: PMID:21784977
  title: Zinc finger protein tristetraprolin interacts with CCL3 mRNA and regulates
    tissue inflammation.
  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:
  - statement: TANK is one of three mutually exclusive adaptors (with SINTBAD and NAP1) that bind the C-terminal coiled-coil of TBK1/IKKepsilon; TBK1 activation in response to virus or poly(I:C) strictly requires the TBK1-TANK interaction. The adaptors occupy distinct subcellular locations.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text not in cache (abstract-only). Establishes TANK's core molecular-adaptor function bridging TBK1/IKKepsilon for type I IFN induction; basis of the IDA molecular adaptor, type I IFN production, and cytoplasm annotations.
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
- id: PMID:24008843
  title: Structure homology and interaction redundancy for discovering virus-host
    protein interactions.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:25852190
  title: Integrative analysis of kinase networks in TRAIL-induced apoptosis provides
    a source of potential targets for combination therapy.
  findings: []
- id: PMID:25861989
  title: TRAF Family Member-associated NF-κB Activator (TANK) Inhibits Genotoxic Nuclear
    Factor κB Activation by Facilitating Deubiquitinase USP10-dependent Deubiquitination
    of TRAF6 Ligase.
  findings:
  - statement: TANK scaffolds a complex with ZC3H12A/MCPIP1 and the deubiquitinase USP10 that mediates USP10-dependent deubiquitination of TRAF6, restraining genotoxic- and IL-1/LPS-induced canonical NF-kappaB activation. CRISPR deletion of TANK enhances NF-kappaB activation, cell survival and cytokine production after genotoxic stress. TANK has no DUB domain of its own.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available in cache. Sole experimental source for the deubiquitinase-scaffold / negative NF-kappaB-regulation annotation set (GO:0035800, GO:0004843 contributes_to, GO:1903003, GO:2000158, GO:0043124, GO:0006974, GO:0071347/0071356/0071479).
- id: PMID:26638075
  title: A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:29251827
  title: Quantitative Proteomics Identified TTC4 as a TBK1 Interactor and a Positive
    Regulator of SeV-Induced Innate Immunity.
  findings: []
- id: PMID:30561431
  title: A protein-protein interaction map of the TNF-induced NF-κB signal transduction
    pathway.
  findings: []
- id: PMID:32707033
  title: Kinase Interaction Network Expands Functional and Disease Roles of Human
    Kinases.
  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:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:8710854
  title: I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal
    transduction.
  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-5362486
  title: 'TANK binds K63-poly-Ub-TRAF3:TICAM1:activated TLR4 '
  findings: []
- id: Reactome:R-HSA-5362500
  title: TANK is ubiquitinated within TANK:K63polyUb-TRAF3:TRIF:activated TLR4
  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-9013985
  title: TANK binds K63-poly-Ub-TRAF3:TICAM1:activated TLR3
  findings: []
- id: Reactome:R-HSA-9013990
  title: TANK is ubiquitinated within TANK:K63polyUb-TRAF3:TICAM1:TLR3:viral dsRNA
  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-933537
  title: Recruitment of TANK to TRAF6
  findings: []
- id: Reactome:R-HSA-933538
  title: Recruitment of IRF7 to TRAF6
  findings: []
- id: Reactome:R-HSA-9705145
  title: TBK1, IKBKE form homodimers
  findings: []
- id: Reactome:R-HSA-9705323
  title: Phosphorylation of TBK1/IKBKE
  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-9823932
  title: 'Recruitment of IKKε (IKBKE) 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-9823939
  title: IKKε (IKBKE) is ubiquitinated within the activated TLR4
  findings: []
- id: Reactome:R-HSA-9824882
  title: IKKε (IKBKE) is phosphorylated within the activated TLR4 complex
  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-9828204
  title: 'IKKε (IKBKE) binds K63-pUb-TANK:K63-pUb-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-9830706
  title: IKKε (IKBKE) is phosphorylated within the activated TLR3 complex
  findings: []
- id: Reactome:R-HSA-9830710
  title: IKKε (IKBKE) is ubiquitinated within the activated TLR3 complex
  findings: []
core_functions:
- description: Functions as a non-catalytic molecular adaptor/scaffold that constitutively
    binds the IKK-related kinases TBK1 and IKBKE (IKKepsilon) and bridges them into
    cytoplasmic signaling complexes that phosphorylate IRF3/IRF7, driving type I interferon
    production during antiviral innate immunity.
  molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:21931631
    supporting_text: TBK1 activation was strictly dependent on the integrity of the TBK1/TANK interaction
  directly_involved_in:
  - id: GO:0032481
    label: positive regulation of type I interferon production
- description: Acts as a scaffold that assembles a deubiquitination complex with ZC3H12A/MCPIP1
    and the deubiquitinase USP10, promoting USP10-dependent deubiquitination of TRAF6
    (and NEMO/IKBKG) to restrain genotoxic- and IL-1/LPS-induced canonical NF-kappaB
    activation. TANK itself has no deubiquitinase activity.
  molecular_function:
    id: GO:0035800
    label: deubiquitinase activator activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:25861989
    supporting_text: which was essential for the USP10-dependent deubiquitination of TRAF6
  directly_involved_in:
  - id: GO:0043124
    label: negative regulation of canonical NF-kappaB signal transduction
- description: Binds the TRAF-C domains of TRAF1/2/3 (originally identified as the TRAF-interacting
    protein I-TRAF) and is the non-catalytic subunit of the TBK1-IKKepsilon-TANK serine/threonine
    kinase complex; phosphorylation by IKBKE disrupts TANK-TRAF2 binding, providing
    a regulatory phospho-switch.
  molecular_function:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:12005438
    supporting_text: TANK binds to the CD40 recognition site on TRAF3
suggested_questions:
- question: How is TANK's dual behaviour - positive regulation of TBK1/IKKepsilon-driven
    type I interferon induction versus negative regulation of canonical NF-kappaB via
    the USP10/ZC3H12A deubiquitination complex - partitioned between stimuli, subcellular
    pools, and post-translational states (phosphorylation by IKBKE, SUMOylation)?
- question: Given that TANK, SINTBAD and NAP1 compete for the same site on TBK1 and
    occupy distinct subcellular locations, what determines which adaptor is used for
    a given TBK1-dependent output (antiviral IFN versus autophagy/selective autophagy)?
suggested_experiments:
- description: Stimulus-resolved interactome (AP-MS/proximity labeling) of endogenous
    TANK under viral/poly(I:C) stimulation versus genotoxic stress and IL-1 to map
    the switch between the TBK1-IKKepsilon kinase complex and the USP10-ZC3H12A deubiquitination
    complex.
- description: Separation-of-function mutants (TBK1-binding-deficient versus TRAF6/ZC3H12A-binding-deficient
    TANK) reconstituted into TANK-knockout cells to independently test the contribution
    of each scaffold function to type I IFN induction and NF-kappaB resolution.