id: Q9NRD1
gene_symbol: FBXO6
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXO6 (FBG2/FBS2, F-box protein that recognizes sugar chains 2) is a 293-amino-acid
  cytoplasmic F-box protein and a member of the FBA (F-box-associated) lectin family
  (FBXO2/FBXO6/FBXO17/FBXO27/FBXO44). It serves as the substrate-recognition subunit
  of SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complexes: its N-terminal F-box domain
  docks onto SKP1 (and thence CUL1-RBX1), while its C-terminal FBA/G domain is a
  carbohydrate-binding lectin module that recognizes N-linked glycans on client
  proteins. As an F-box protein FBXO6 has no intrinsic catalytic activity; catalysis
  is contributed by the RING subunit RBX1 within the assembled SCF complex, and FBXO6
  confers substrate specificity. Through its FBA domain FBXO6 binds high-mannose
  oligosaccharides (with the chitobiose core being essential), complex-type glycans,
  and sulfated glycoproteins, and it preferentially engages denatured/misfolded
  glycoproteins. This lectin activity directs misfolded glycoproteins that have been
  retrotranslocated to the cytosol into the endoplasmic-reticulum-associated
  degradation (ERAD)/glycoprotein-quality-control pathway, promoting their
  ubiquitination and proteasomal degradation. FBXO6 also has a documented role in the
  DNA replication/damage checkpoint: it recognizes activated, S345-phosphorylated CHEK1
  (CHK1) via its FBA domain and assembles an SCF(FBXO6) complex that ubiquitinates CHK1
  and targets it for degradation, contributing to checkpoint termination and influencing
  cellular sensitivity to replication stress. FBXO6 is broadly but variably expressed
  (notably in liver and kidney) and interacts with VCP/p97. Among its glycoprotein
  clients, SCF(FBXO6/Fbs2) ubiquitinates the ER-membrane transcription factor
  NFE2L1/NRF1; in the absence of the cytoplasmic deglycosylase NGLY1, FBXO6-mediated
  ubiquitination of still-glycosylated NFE2L1 impairs its processing and nuclear
  function, blunting the proteasome "bounce-back" induction of new proteasome
  subunits, and genetic reduction of Fbs2/FBXO6 partially rescues Ngly1-knockout
  phenotypes in mice (with Fbs2-knockout mice otherwise healthy).
existing_annotations:
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of involvement in ER-associated degradation, a core biological process of the FBA lectin family of F-box proteins.
    action: ACCEPT
    reason: Core biological process; FBXO6 recognizes glycans on misfolded glycoproteins to direct them to ERAD/proteasomal degradation, supported by UniProt and ISS.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: Involved in endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins by recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic assignment of cytoplasmic localization, consistent with the documented cytoplasmic site of FBXO6 action.
    action: ACCEPT
    reason: Correct localization; SCF(FBXO6) acts in the cytosol on retrotranslocated glycoproteins and on cytoplasmic CHK1; supported by IDA (PMID:19716789) and UniProt subcellular location.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789}'
- term:
    id: GO:0006516
    label: glycoprotein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of involvement in glycoprotein catabolism, a core process for this lectin F-box family that targets glycoproteins for degradation.
    action: ACCEPT
    reason: Core biological process; FBXO6 recognizes glycans on misfolded glycoproteins and routes them to degradation.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic assignment placing FBXO6 in the SCF (SKP1-CUL1-F-box) ubiquitin ligase complex, its defining structural context as an F-box protein.
    action: ACCEPT
    reason: Core cellular-complex assignment; FBXO6 assembles into a canonical SCF complex (SKP1, CUL1, RBX1) via its F-box domain, supported experimentally.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: All FBA family members co-immunoprecipitated components of the SCF complex
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of involvement in SCF-dependent proteasomal degradation, the core biological process executed by SCF(FBXO6).
    action: ACCEPT
    reason: Core biological process; FBXO6 acts as the substrate receptor of an SCF complex that drives proteasomal degradation of its glycoprotein and CHK1 substrates.
    supported_by:
    - reference_id: PMID:19716789
      supporting_text: an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic assignment to the ER quality-control compartment, inferred from the family's role in glycoprotein quality control/ERAD.
    action: KEEP_AS_NON_CORE
    reason: Plausible localization inferred from the ERAD/glycoprotein-QC role, but FBXO6 is a cytoplasmic protein that engages substrates after retrotranslocation; direct ERQC localization is not demonstrated for FBXO6.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: Phylogenetic assignment of ubiquitin protein ligase activity with a contributes_to qualifier, reflecting that FBXO6 is the substrate receptor that contributes to the activity of the assembled SCF E3 ligase rather than carrying catalytic activity itself.
    action: KEEP_AS_NON_CORE
    reason: FBXO6 has no intrinsic catalytic ligase activity; catalysis resides in the RING subunit RBX1. The contributes_to qualifier is the correct way to capture that FBXO6 contributes substrate specificity to SCF ligase activity, but FBXO6's own core molecular function is carbohydrate binding, so this is retained as non-core rather than as the gene's primary function.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: As the substrate recognition subunits of multiprotein ubiquitin ligase complexes, F-box proteins have no intrinsic catalytic activity of their own.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Combined automated electronic assignment of cytoplasmic localization, consistent with the experimentally documented cytoplasmic site of FBXO6.
    action: ACCEPT
    reason: Correct localization; redundant with the IDA (PMID:19716789) and IBA cytoplasm annotations.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789}'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23108047
  qualifier: enables
  review:
    summary: IntAct interaction with CUL1 (Q13616), the cullin scaffold of the SCF complex. A real and functionally relevant interaction, but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXO6-CUL1 SCF-assembly interaction, but bare protein binding is uninformative per curation guidelines; the SCF-complex membership is captured by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'Q9NRD1; Q13616: CUL1; NbExp=6; IntAct=EBI-3938499, EBI-359390'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27705803
  qualifier: enables
  review:
    summary: IntAct interaction with SKP1 (P63208), the adaptor that bridges the F-box domain to CUL1. A real SCF-assembly interaction, but bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXO6-SKP1 interaction central to SCF assembly, but bare protein binding is uninformative; SCF membership is captured by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'Q9NRD1; P63208: SKP1; NbExp=10; IntAct=EBI-3938499, EBI-307486'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput interactome interaction with CUL1 (Q13616). A real SCF-component interaction, but bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXO6-CUL1 interaction but bare protein binding is uninformative; captured at the complex level by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'Q9NRD1; Q13616: CUL1; NbExp=6; IntAct=EBI-3938499, EBI-359390'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30833792
  qualifier: enables
  review:
    summary: Interferon-stimulated-gene interactome capturing FBXO6 interactions with SKP1 (P63208), CUL1 (Q13616) and LGALS3BP (Q08380, a secreted glycoprotein). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records SCF-component interactions plus a glycoprotein (LGALS3BP) interaction, but bare protein binding is uninformative; relevant functions are captured by the SCF-complex and carbohydrate-binding annotations.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'Q9NRD1; Q08380: LGALS3BP; NbExp=2; IntAct=EBI-3938499, EBI-354956'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome reference map capturing the FBXO6-SKP1 (P63208) interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXO6-SKP1 interaction but bare protein binding is uninformative; SCF membership is captured by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'Q9NRD1; P63208: SKP1; NbExp=10; IntAct=EBI-3938499, EBI-307486'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Cell-specific interactome capturing FBXO6 interactions with SKP1 (P63208) and CUL1 (Q13616). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records SCF-component interactions but bare protein binding is uninformative; captured at the complex level by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'Q9NRD1; P63208: SKP1; NbExp=10; IntAct=EBI-3938499, EBI-307486'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map interactome capturing FBXO6 interactions with SKP1 (P63208) and CUL1 (Q13616). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records SCF-component interactions but bare protein binding is uninformative; captured at the complex level by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'Q9NRD1; Q13616: CUL1; NbExp=6; IntAct=EBI-3938499, EBI-359390'
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment of ubiquitin-dependent protein catabolism, a parent process consistent with FBXO6's role as an SCF substrate receptor.
    action: ACCEPT
    reason: Correct but generic; the more specific GO:0031146 (SCF-dependent proteasomal ubiquitin-dependent catabolism) and GO:0036503 (ERAD) better capture the core role.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: promoting their ubiquitination and subsequent degradation
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: Ortholog-based electronic assignment of SCF complex membership, the defining context of FBXO6 as an F-box protein.
    action: ACCEPT
    reason: Core cellular-complex assignment; redundant with the IBA, NAS and IDA SCF-complex annotations and experimentally supported.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: All FBA family members co-immunoprecipitated components of the SCF complex
- term:
    id: GO:0030246
    label: carbohydrate binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-based electronic assignment of carbohydrate binding, capturing the FBA/G-domain lectin activity that is the core molecular function distinguishing this F-box subfamily.
    action: ACCEPT
    reason: Core molecular function; the FBA domain is a lectin that binds high-mannose, complex and sulfated glycans, directly demonstrated by glycan-array and pulldown assays.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: FBXO6 bound high mannose glycans with relatively high affinity
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment of SCF-dependent proteasomal degradation, the core process executed by SCF(FBXO6).
    action: ACCEPT
    reason: Core biological process; redundant with the IBA, NAS and IDA annotations of the same term.
    supported_by:
    - reference_id: PMID:19716789
      supporting_text: an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment of involvement in ERAD, a core biological process for FBXO6.
    action: ACCEPT
    reason: Core biological process; redundant with the IBA and ISS ERAD annotations.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: Involved in endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-based electronic assignment to the ER quality-control compartment, inferred from the glycoprotein-QC/ERAD role.
    action: KEEP_AS_NON_CORE
    reason: Plausible but not directly demonstrated for FBXO6, which is a cytoplasmic protein engaging substrates after retrotranslocation; the experimentally supported localization is cytoplasm.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789}'
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: contributes_to
  review:
    summary: Ortholog-based electronic assignment of ubiquitin protein ligase activity with a contributes_to qualifier, reflecting FBXO6's contribution of substrate specificity to the SCF E3 ligase.
    action: KEEP_AS_NON_CORE
    reason: FBXO6 has no intrinsic catalytic ligase activity (RBX1 is catalytic); the contributes_to qualifier correctly conveys that FBXO6 contributes substrate recognition to SCF ligase activity, but the gene's own core molecular function is carbohydrate binding.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: As the substrate recognition subunits of multiprotein ubiquitin ligase complexes, F-box proteins have no intrinsic catalytic activity of their own.
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-derived general protein ubiquitination process, a parent of the specific SCF-dependent ubiquitination FBXO6 contributes to.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific SCF-dependent proteasomal catabolism and ERAD annotations better capture FBXO6's role.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    summary: ComplexPortal/Reactome non-traceable author statement placing FBXO6 in an SCF E3 ubiquitin ligase complex; consistent with a defined ComplexPortal entry (CPX-7905, SCF FBXO6 variant).
    action: ACCEPT
    reason: Core cellular-complex assignment; FBXO6 is a defined F-box substrate-receptor variant of the SCF complex, supported experimentally (PMID:18203720) and by ComplexPortal CPX-7905.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: ComplexPortal; CPX-7905; SCF E3 ubiquitin ligase complex, FBXO6 variant.
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: involved_in
  review:
    summary: ComplexPortal non-traceable author statement of involvement in SCF-dependent proteasomal degradation, the core process of SCF complexes including SCF(FBXO6).
    action: ACCEPT
    reason: Core biological process; redundant with the IBA, IEA and IDA annotations of the same term.
    supported_by:
    - reference_id: PMID:34445249
      supporting_text: SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization within a CRL1/neddylation reaction (NEDD8 transfer to CRL1). Consistent with the cytoplasmic localization of FBXO6 and its SCF complex.
    action: ACCEPT
    reason: Correct localization; the cytosol is a child of cytoplasm and consistent with the experimentally supported cytoplasmic localization; these Reactome cytosol annotations reflect generic CRL/neddylation machinery reactions.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789}'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization within a CRL1/neddylation reaction. Consistent with FBXO6's cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization (cytosol is part of cytoplasm); reflects generic CRL/neddylation reactions and is redundant with the experimentally supported cytoplasm annotation.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789}'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (CAND1 binds cytosolic CRL E3 ligases). Consistent with FBXO6's cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic CRL-regulation machinery reactions.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789}'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (COMMDs displace CAND1 from cytosolic CRL complexes). Consistent with FBXO6's cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic CRL-regulation machinery reactions.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789}'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (COP9 signalosome deneddylates cytosolic CRL complexes). Consistent with FBXO6's cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic CRL-regulation machinery reactions.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789}'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (MyrG-DCUN1D3 binds CRL1 complex). Consistent with FBXO6's cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic CRL-regulation machinery reactions.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789}'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization within a generic ubiquitination reaction (transfer of Ub from E2 to substrate). Consistent with FBXO6's cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic SCF ubiquitination-reaction machinery.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789}'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization within a generic ubiquitination reaction (release of E3 from polyubiquitinated substrate). Consistent with FBXO6's cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic SCF ubiquitination-reaction machinery.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789}'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization within a generic ubiquitination reaction (polyubiquitination of substrate). Consistent with FBXO6's cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic SCF ubiquitination-reaction machinery.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789}'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization within a generic ubiquitination reaction (interaction of E3 with substrate and E2-Ub complex). Consistent with FBXO6's cytoplasmic localization.
    action: ACCEPT
    reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic SCF ubiquitination-reaction machinery.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789}'
- term:
    id: GO:0000077
    label: DNA damage checkpoint signaling
  evidence_type: TAS
  original_reference_id: PMID:19716789
  qualifier: involved_in
  review:
    summary: Traceable author statement linking FBXO6 to the DNA damage/replication checkpoint via SCF(FBXO6)-mediated ubiquitination and degradation of activated CHK1, which terminates the checkpoint.
    action: KEEP_AS_NON_CORE
    reason: Well-supported, genuine role (degradation of activated CHK1 contributes to checkpoint termination), but distinct from the gene's primary glycan-recognition/ERAD core function; retained as a non-core second process.
    supported_by:
    - reference_id: PMID:19716789
      supporting_text: DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19716789
  qualifier: enables
  review:
    summary: IPI interaction with CHEK1/CHK1 (O14757), a functionally important FBXO6 substrate engaged via the FBA domain. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally meaningful FBXO6-CHK1 substrate interaction, but bare protein binding is uninformative; the CHK1-regulation role is captured by the checkpoint/SCF-catabolism annotations.
    supported_by:
    - reference_id: PMID:19716789
      supporting_text: endogenous Fbx6 was co-immunoprecipitated with Chk1 in extracts from non-transfected cells
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:19716789
  qualifier: located_in
  review:
    summary: Direct experimental evidence (immunolocalization) that FBXO6 is mainly localized to the cytoplasm, where it engages CHK1.
    action: ACCEPT
    reason: Core localization with direct experimental support; FBXO6 acts in the cytoplasm/cytosol on its substrates.
    supported_by:
    - reference_id: PMID:19716789
      supporting_text: The Fbx6-Chk1 interaction was only detected in the cytoplasmic compartment where Fbx6 is mainly localized
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: TAS
  original_reference_id: PMID:19716789
  qualifier: involved_in
  review:
    summary: Traceable author statement annotating FBXO6 to DNA repair, derived from its role in the ATR-CHK1 replication-checkpoint pathway that coordinates DNA damage/repair responses.
    action: MARK_AS_OVER_ANNOTATED
    reason: FBXO6's documented role is checkpoint termination via CHK1 degradation, not DNA repair per se; CHK1 activation triggers repair responses, but FBXO6 acts to remove activated CHK1 and is not itself a repair factor. DNA damage checkpoint signaling (GO:0000077) more accurately captures the role; DNA repair is an over-annotation of the downstream pathway.
    supported_by:
    - reference_id: PMID:19716789
      supporting_text: which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:19716789
  qualifier: part_of
  review:
    summary: Direct experimental evidence that FBXO6 forms an SCF (SKP1-CUL1-FBXO6) complex, demonstrated by co-immunoprecipitation of SCF components.
    action: ACCEPT
    reason: Core cellular-complex assignment with direct experimental support.
    supported_by:
    - reference_id: PMID:19716789
      supporting_text: an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:19716789
  qualifier: involved_in
  review:
    summary: Direct experimental evidence that SCF(FBXO6) drives the ubiquitination and proteasomal degradation of CHK1, demonstrating involvement in SCF-dependent proteasomal catabolism.
    action: ACCEPT
    reason: Core biological process with direct experimental (IDA) support; FBXO6 FL supported CHK1 ubiquitination in vitro and FBXO6 depletion stabilized CHK1.
    supported_by:
    - reference_id: PMID:19716789
      supporting_text: only the Fbx6 FL protein supported ubiquitination of Chk1 in vitro
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity-based assignment of involvement in ERAD, transferred from the mouse ortholog (Q9QZN4); a core biological process.
    action: ACCEPT
    reason: Core biological process; consistent with the IBA and IEA ERAD annotations and the documented glycan-recognition/glycoprotein-degradation function.
    supported_by:
    - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
      supporting_text: Involved in endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: involved_in
  review:
    summary: Early traceable author statement (F-box family identification paper) annotating FBXO6 to proteolysis, reflecting the general role of F-box proteins in SCF-mediated protein degradation.
    action: KEEP_AS_NON_CORE
    reason: Correct but very generic; the specific SCF-dependent proteasomal catabolism and ERAD annotations better capture FBXO6's role. The abstract describes the F-box family broadly rather than FBXO6 specifically.
    supported_by:
    - reference_id: PMID:10531035
      supporting_text: F-box proteins are one of the four subunits of ubiquitin protein ligases called SCFs
references:
- 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:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10531035
  title: Identification of a family of human F-box proteins.
  findings:
  - statement: FBXO6 was identified as one of a family of 26 human F-box proteins; F-box proteins are substrate-recognition subunits of SCF ubiquitin ligases.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Original identification of human FBXO6 (Fbx6) within the F-box family; abstract-only. Source of the generic proteolysis (TAS) annotation; describes the family rather than FBXO6-specific function.
- id: PMID:18203720
  title: Diversity in tissue expression, substrate binding, and SCF complex formation
    for a lectin family of ubiquitin ligases.
  findings:
  - statement: FBXO6 is a member of the FBA lectin family whose conserved G/FBA domain binds high-mannose, complex and sulfated glycans (chitobiose core essential); a Y241/W242 hydrophobic pocket is required for glycan binding, and FBXO6 co-precipitates SCF components (SKP1, CUL1, RBX1). F-box proteins have no intrinsic catalytic activity.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; directly establishes FBXO6's lectin (carbohydrate-binding) molecular function, SCF complex formation, and the absence of intrinsic F-box catalytic activity. Primary support for the carbohydrate-binding and SCF-complex annotations.
- id: PMID:19716789
  title: The F box protein Fbx6 regulates Chk1 stability and cellular sensitivity
    to replication stress.
  findings:
  - statement: FBXO6 (Fbx6) is the substrate-recognition subunit of an SCF (SKP1-CUL1-FBXO6) E3 ligase that, via its FBA domain, binds activated CHK1 and mediates CHK1 ubiquitination and degradation to terminate the replication checkpoint; FBXO6 is mainly cytoplasmic and its level inversely correlates with CHK1 and modulates camptothecin sensitivity.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; sole experimental source for the CHK1-regulation/DNA-damage-checkpoint role, SCF(FBXO6) complex (IDA), cytoplasm (IDA), and SCF-dependent catabolism (IDA) annotations.
- id: PMID:23108047
  title: FBXW7-mediated degradation of CCDC6 is impaired by ATM during DNA damage
    response in lung cancer cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Source of an IntAct FBXO6-CUL1 interaction (bare protein binding); abstract is centered on FBXW7/CCDC6, the FBXO6-CUL1 binding datum derives from the associated interaction dataset.
- id: PMID:27705803
  title: A High-Density Map for Navigating the Human Polycomb Complexome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of an FBXO6-SKP1 bare protein binding annotation.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of an FBXO6-CUL1 bare protein binding annotation.
- id: PMID:30833792
  title: A protein-interaction network of interferon-stimulated genes extends the
    innate immune system landscape.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: ISG interactome; source of FBXO6 interactions with SKP1, CUL1 and the secreted glycoprotein LGALS3BP (bare protein binding).
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Binary interactome reference map; source of an FBXO6-SKP1 bare protein binding annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cell-specific interactome; source of FBXO6-SKP1/CUL1 bare protein binding annotations.
- id: PMID:34445249
  title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  findings:
  - statement: The SCF complex comprises ~69 SCF E3 ubiquitin ligase complexes distinguished by variable F-box proteins that determine substrate specificity and target substrates for proteasomal degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Review (abstract-only in cache); used by ComplexPortal as NAS support for FBXO6 SCF-complex membership and SCF-dependent catabolism. Describes SCF complexes generally.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map interactome; source of FBXO6-SKP1/CUL1 bare protein binding annotations.
- id: Reactome:R-HSA-8952618
  title: AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8952620
  title: NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8955241
  title: CAND1 binds cytosolic CRL E3 ubiquitin ligases
  findings: []
- id: Reactome:R-HSA-8955289
  title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956040
  title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956200
  title: MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-983140
  title: Transfer of Ub from E2 to substrate and release of E2
  findings: []
- id: Reactome:R-HSA-983147
  title: Release of E3 from polyubiquitinated substrate
  findings: []
- id: Reactome:R-HSA-983156
  title: Polyubiquitination of substrate
  findings: []
- id: Reactome:R-HSA-983157
  title: Interaction of E3 with substrate and E2-Ub complex
  findings: []
- id: file:human/FBXO6/FBXO6-deep-research-falcon.md
  title: Falcon deep research report for human FBXO6
  findings:
  - statement: FBXO6 (FBS2) is the substrate-recognition module of an SCF-type (SCF^FBS2 / SCF^FBXO6) ubiquitin ligase that ubiquitinates N-glycoprotein substrates in protein quality control.
    supporting_text: FBXO6 (FBS2) is discussed as an F-box protein that serves as the substrate-recognition module of an SCF-type ubiquitin ligase (**SCF^FBS2 / SCF^FBXO6**), enabling ubiquitination of selected substrates, including **N-glycoproteins** involved in protein quality control.
  - statement: In the NGLY1/ERAD axis, SCF^FBS2 ubiquitinates ERAD glycoprotein substrates including the transcription factor NFE2L1/NRF1, which are then degraded by the proteasome after deglycosylation by NGLY1.
    supporting_text: ERAD glycoprotein substrates (including the transcription factor **NFE2L1/NRF1**) are ubiquitinated by multiple E3 ligases, including **SCF^FBS2**, and then degraded by the proteasome; in typical conditions, many ubiquitinated glycoproteins are thought to be **deglycosylated by NGLY1 during proteasomal degradation**.
  - statement: When NGLY1 is absent, SCF^FBS2-mediated ubiquitination of NFE2L1 impairs its processing/nuclear function and blocks induction of proteasome subunits (the proteasome bounce-back response), contributing to proteasome dysfunction.
    supporting_text: in the **absence of NGLY1**, SCF^FBS2-mediated ubiquitination of NFE2L1 is linked to impaired NFE2L1 processing/nuclear function and failure to induce proteasome subunits, contributing to chronic proteasome compromise and cytotoxicity.
  - statement: SCF^FBS2 acts in the cytosolic/proteasomal arm of ERAD after retrotranslocation; ubiquitinated N-glycoproteins accumulate in the cytosol when NGLY1 is absent.
    supporting_text: The mechanistic model places SCF^FBS2 activity in the **cytosolic/proteasomal degradation pathway for ERAD substrates** (i.e., after retrotranslocation from the ER lumen), and describes **accumulation of SCF^FBS2-ubiquitinated N-glycoproteins in the cytosol** when NGLY1 is absent.
  - statement: Genetic reduction of Fbs2/FBXO6 partially rescues Ngly1-knockout lethality in mice, and Fbs2-knockout mice are otherwise healthy, motivating FBS2 inhibition as a therapeutic concept for NGLY1 deficiency.
    supporting_text: genetic reduction of FBS2/FBXO6** can partially rescue lethality/phenotypes associated with **Ngly1 knockout**, and that **Fbs2 knockout mice are reported as healthy** in that review context.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Falcon synthesis anchored on a peer-reviewed NGLY1 rodent-model review (Fujihira, Asahina & Suzuki, J Biochem 2022). Establishes a concrete PN-relevant glycoprotein substrate (NFE2L1/NRF1) and the NGLY1/proteasome-bounce-back link; cross-checked against the FBA-lectin/ERAD mechanism in UniProt and PMID:18203720. Cancer prognostic-signature claims (breast, HCC) are association-level and treated as leads only.
core_functions:
- description: Carbohydrate-binding (lectin) substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase; via its FBA/G domain FBXO6 binds N-linked high-mannose and complex/sulfated glycans on misfolded glycoproteins and, as part of the SCF complex, directs them to ubiquitination and proteasomal degradation in the glycoprotein-quality-control/ERAD pathway.
  molecular_function:
    id: GO:0030246
    label: carbohydrate binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:18203720
    supporting_text: FBXO6 bound high mannose glycans with relatively high affinity
  - reference_id: file:human/FBXO6/FBXO6-uniprot.txt
    supporting_text: recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation
  - reference_id: file:human/FBXO6/FBXO6-deep-research-falcon.md
    supporting_text: ERAD glycoprotein substrates (including the transcription factor **NFE2L1/NRF1**) are ubiquitinated by multiple E3 ligases, including **SCF^FBS2**, and then degraded by the proteasome; in typical conditions, many ubiquitinated glycoproteins are thought to be **deglycosylated by NGLY1 during proteasomal degradation**.
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
- description: Substrate receptor of an SCF(FBXO6) E3 ligase that recognizes activated, S345-phosphorylated CHEK1/CHK1 through its FBA domain and targets it for ubiquitination and proteasomal degradation, contributing to termination of the DNA replication/damage checkpoint and modulating cellular sensitivity to replication stress.
  molecular_function:
    id: GO:0030246
    label: carbohydrate binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:19716789
    supporting_text: an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint
  directly_involved_in:
  - id: GO:0000077
    label: DNA damage checkpoint signaling
proposed_new_terms: []
suggested_questions:
- question: Does FBXO6 recognize the CHK1 degron purely through a protein-protein (FBA-domain) interaction, or is glycan recognition also involved, and is the glycan-binding pocket (Y241/W242) dispensable for CHK1 targeting?
- question: What is the endogenous repertoire of glycoprotein substrates degraded specifically via SCF(FBXO6) (versus the paralog FBXO2), and how does FBXO6's broader specificity for complex and sulfated glycans translate into distinct in vivo substrates?
- question: How is partitioning between FBXO6's glycoprotein-ERAD role and its CHK1-checkpoint role regulated, and does the FBXO6-VCP/p97 interaction couple substrate recognition to retrotranslocation?
- question: Does SCF(FBXO6) ubiquitination of NFE2L1/NRF1 depend on the glycan-binding (FBA lectin) pocket, and is the proteasome bounce-back defect in NGLY1 deficiency driven specifically by FBXO6-mediated targeting of still-glycosylated NFE2L1?
suggested_experiments:
- description: Perform quantitative ubiquitinome/proteome profiling in FBXO6-knockout versus wild-type cells, with and without ER stress and replication stress (e.g. camptothecin), to define the endogenous SCF(FBXO6) substrate repertoire and distinguish glycoprotein from CHK1-dependent effects.
- description: Reconstitute SCF(FBXO6) ubiquitination in vitro with purified SKP1, CUL1, RBX1, an E2 and FBXO6, comparing wild-type FBXO6 with the Y241A/W242A glycan-pocket mutant against a high-mannose glycoprotein substrate and against phospho-CHK1 to dissect glycan-dependent versus glycan-independent substrate targeting.
- description: Use glycan-array and structural (crystallography/cryo-EM) analysis of the FBXO6 FBA domain bound to defined oligosaccharides to map the determinants of its broader specificity (high-mannose, complex, sulfated glycans) relative to FBXO2.