id: Q9UK22
gene_symbol: FBXO2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXO2 (FBG1/FBX2/NFB42) is a 296-residue cytoplasmic F-box protein that serves
  as the substrate-recognition subunit of a Skp1-Cul1-F-box (SCF) E3
  ubiquitin-protein ligase complex. It contains an N-terminal F-box domain
  (residues 44-91) that binds SKP1, bridging the receptor to the CUL1-RBX1
  catalytic core, and a C-terminal F-box-associated (FBA) sugar-binding domain
  (residues 113-296) that folds as a galactose-binding-domain-like lectin and
  binds N-linked high-mannose oligosaccharides. The FBA domain recognizes the
  innermost N-glycan core (Man3GlcNAc2 / the chitobiose-proximal GlcNAc2 moiety)
  through a small hydrophobic pocket, a "sugar degron" that becomes exposed when
  a glycoprotein is misfolded, denatured, or aberrantly retrotranslocated to the
  cytosol. Through this lectin activity FBXO2 recognizes N-glycans on
  misfolded/denatured glycoproteins that have been retrotranslocated from the
  endoplasmic reticulum into the cytosol, recruiting them to the SCF complex for
  polyubiquitination and proteasomal degradation as part of the ER-associated
  degradation (ERAD) pathway, thereby preventing the accumulation of cytosolic
  aggregates of unfolded glycoproteins. Reported glycoprotein clients in the
  Fbs1/Fbs2 quality-control orbit include pre-integrin beta-1, the T-cell
  receptor alpha chain, the asialoglycoprotein receptor subunit, and the disease
  variant CFTR-deltaF508; in neurons FBXO2 additionally turns over APP and BACE1
  to limit amyloidogenic processing. FBXO2 is most
  highly expressed in the nervous system, where it has additional roles in
  synaptic protein turnover and in clearance of damaged glycan-bearing membranes
  (lysophagy) and intracellular bacteria (xenophagy), recognizing GlcNAc/high-
  mannose glycans on these targets. The protein is a peripheral cytoplasmic-side
  membrane protein and is itself a glycoprotein-specific lectin, not a
  glycosidase.
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 for the FBA/lectin F-box family.
    action: ACCEPT
    reason: Core biological process; FBXO2 recognizes N-glycans on retrotranslocated misfolded glycoproteins and targets them for ERAD, supported by UniProt and the founding literature. The Falcon deep-research synthesis reinforces the mechanism (recognition of the innermost N-glycan core after ER retrotranslocation) and adds named ERAD clients.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Involved in the 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
    - reference_id: file:human/FBXO2/FBXO2-deep-research-falcon.md
      supporting_text: lectin-type F-box proteins such as FBXO2 are described as operating in the **nucleocytoplasmic compartment**, where they can recognize **retrotranslocated ER glycoproteins** and promote their ubiquitination as part of **ER-associated degradation (ERAD)** and broader proteostasis mechanisms
- 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 site of action, consistent with FBXO2 acting on retrotranslocated cytosolic glycoproteins.
    action: ACCEPT
    reason: FBXO2 is a cytoplasmic protein that acts on the cytosolic side; supported by UniProt and IDA evidence.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- 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, the substrate-class-defining process for this lectin F-box subfamily.
    action: ACCEPT
    reason: Core process; FBXO2 directs ubiquitin-dependent degradation of N-glycosylated substrates recognized via its FBA lectin domain.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-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 of FBXO2 as part of the SCF complex, its core complex context as a substrate receptor.
    action: ACCEPT
    reason: Core; FBXO2 is the substrate-recognition subunit of SCF(FBXO2) (CUL1, RBX1, SKP1, FBXO2).
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2
- 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 SCF-dependent proteasomal degradation, the core process executed by SCF(FBXO2).
    action: ACCEPT
    reason: Core biological process; SCF(FBXO2) mediates ubiquitination and proteasomal degradation of its glycoprotein substrates.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins
- 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 ligase activity with the contributes_to qualifier, reflecting FBXO2's role as a non-catalytic receptor subunit within the SCF ligase whose catalytic activity resides in RBX1.
    action: ACCEPT
    reason: Appropriate with contributes_to; FBXO2 is the substrate-recognition subunit and does not itself carry the catalytic RING activity (RBX1), but contributes to the complex's ligase function.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of cytoplasmic localization, consistent with the experimentally and curator-supported cytoplasmic location.
    action: ACCEPT
    reason: Correct core localization; redundant with IDA and UniProt.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: High-throughput interactome interaction. Bare protein binding is uninformative per curation guidelines.
    action: KEEP_AS_NON_CORE
    reason: Records a real screen-derived interaction but bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'Q9UK22; P63208: SKP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27705803
  qualifier: enables
  review:
    summary: Interaction captured in a Polycomb complexome map. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'Q9UK22; O15212: PFDN6'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome reference map interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'Q9UK22; P63208: SKP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Cell-specific interactome interaction. 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/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'Q9UK22; P63208: SKP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput cell-map interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'Q9UK22; P63208: SKP1'
- term:
    id: GO:0001540
    label: amyloid-beta binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-based electronic transfer of amyloid-beta binding. FBXO2 has been reported to bind/regulate APP-derived species, but this is a context-specific neuronal activity rather than the core lectin/ERAD function.
    action: KEEP_AS_NON_CORE
    reason: Plausible secondary neuronal activity (FBXO2 regulates APP/amyloid-related substrates) but not the core carbohydrate-binding/ERAD function; retained as non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-based electronic assignment of cytosolic localization, consistent with the cytoplasmic/cytosolic site of action.
    action: ACCEPT
    reason: Correct localization; FBXO2 acts on the cytosolic side; redundant with UniProt ISS and IDA.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic assignment of protein ubiquitination, a parent process of the specific SCF-dependent catabolism FBXO2 mediates.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific SCF-dependent proteasomal catabolism and ERAD annotations better capture the role.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- 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 core complex context.
    action: ACCEPT
    reason: Core; redundant with IBA/ISS/NAS SCF annotations.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2
- term:
    id: GO:0030246
    label: carbohydrate binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Electronic assignment (UniProt keyword Lectin) of carbohydrate binding, the defining molecular function of the FBA domain.
    action: ACCEPT
    reason: Core molecular function; the FBA domain is a lectin that binds N-linked high-mannose glycans (carbohydrate-binding sites at residues 210-212 and 278-279). The Falcon deep-research synthesis specifies that the bound determinant is the innermost N-glycan core (Man3GlcNAc2) engaged by a hydrophobic pocket, with preference for high-mannose glycans on denatured glycoproteins.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Able to recognize and bind denatured glycoproteins, preferentially those of the high-mannose type
    - reference_id: file:human/FBXO2/FBXO2-deep-research-falcon.md
      supporting_text: it binds the **innermost N-glycan core** (described as **Man3GlcNAc2** / innermost GlcNAc2 moiety) using a **small hydrophobic pocket** in its SBD, with preference for **high-mannose N-glycans** and **denatured/misfolded glycoproteins** (where the core glycan becomes accessible)
- 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 catabolism, the core process.
    action: ACCEPT
    reason: Core biological process; redundant with IBA/ISS/NAS evidence.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins
- term:
    id: GO:0043197
    label: dendritic spine
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-based electronic transfer of dendritic spine localization, reflecting FBXO2's neuronal/synaptic expression and role in synaptic protein turnover.
    action: KEEP_AS_NON_CORE
    reason: Plausible neuronal localization tied to a secondary synaptic role; not the core ERAD compartment.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Ortholog-based electronic transfer of glutamatergic synapse localization/activity, reflecting a neuronal synaptic role.
    action: KEEP_AS_NON_CORE
    reason: Secondary neuronal/synaptic context; not the core ERAD/lectin function.
- term:
    id: GO:0099576
    label: regulation of protein catabolic process at postsynapse, modulating synaptic transmission
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic transfer of a postsynaptic protein-catabolism regulatory role, reflecting FBXO2's neuronal function in synaptic protein turnover.
    action: KEEP_AS_NON_CORE
    reason: Secondary, neuronal-context process; not the core ERAD/glycoprotein catabolism function.
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    summary: Author-stated SCF complex membership. Core complex context.
    action: ACCEPT
    reason: Core; consistent with the SCF(FBXO2) complex composition.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2
- 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: Author-stated involvement in SCF-dependent proteasomal degradation. Core process.
    action: ACCEPT
    reason: Core biological process; consistent with FBXO2's SCF substrate-receptor function.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins
- term:
    id: GO:1904415
    label: regulation of xenophagy
  evidence_type: NAS
  original_reference_id: PMID:34515398
  qualifier: involved_in
  review:
    summary: FBXO2/SCF directs xenophagy against group A Streptococcus by recognizing GlcNAc side chains of the bacterial surface carbohydrate; FBXO2 knockout reduces ubiquitin accumulation and xenophagic degradation. A documented secondary (immune/autophagy) role of the lectin activity.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported secondary role extending the lectin/glycan-recognition function to bacterial glycans; distinct from the core ERAD function.
    supported_by:
    - reference_id: PMID:34515398
      supporting_text: FBXO2, a glycoprotein-specific receptor for substrate in the SKP1/CUL1/F-box protein (SCF) ubiquitin ligase complex, mediates recognition of GlcNAc side chains of the GAS surface carbohydrate structure and promotes ubiquitin-mediated xenophagy against GAS
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:21378169
  qualifier: located_in
  review:
    summary: Direct assay placing FBXO2 in the cytoplasm in the study of Skp1/CRM1-controlled F-box protein localization. Core localization.
    action: ACCEPT
    reason: IDA-supported cytoplasmic localization consistent with the documented site of action.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome neddylation-pathway annotation of cytosolic localization for the CRL1/SCF context. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant with IDA/ISS evidence.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome CRL1/neddylation cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant with other evidence.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome (CAND1 binds cytosolic CRL) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome (COMMD/CAND1) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome (COP9 signalosome deneddylation) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome (DCUN1D3 binds CRL1) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome (Transfer of Ub from E2 to substrate) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome (Release of E3 from polyubiquitinated substrate) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome (Polyubiquitination of substrate) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome (Interaction of E3 with substrate and E2-Ub) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Curator sequence-similarity transfer of cytosolic localization. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant with IDA.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0006516
    label: glycoprotein catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Curator sequence-similarity transfer of glycoprotein catabolic process, the substrate-class-defining core process.
    action: ACCEPT
    reason: Core process; redundant with IBA.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-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:0016567
    label: protein ubiquitination
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Curator sequence-similarity transfer of protein ubiquitination, a parent of the specific SCF-dependent catabolism.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; specific SCF-dependent catabolism/ERAD annotations are preferred.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    summary: Curator sequence-similarity transfer of SCF complex membership. Core complex context.
    action: ACCEPT
    reason: Core; redundant with IBA/IEA/NAS.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Curator sequence-similarity transfer of SCF-dependent proteasomal catabolism. Core process.
    action: ACCEPT
    reason: Core biological process; redundant with IBA/IEA/NAS.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: enables
  review:
    summary: Author statement from the F-box family identification paper attributing ubiquitin-protein transferase activity to the SCF complex containing this F-box protein. FBXO2 itself is the substrate receptor, not the catalytic subunit.
    action: KEEP_AS_NON_CORE
    reason: The catalytic transferase activity resides in the RBX1/CUL1 core, not the F-box receptor; this term over-attributes catalysis to FBXO2. Retained as non-core (contributes_to ligase activity is the more accurate framing).
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: involved_in
  review:
    summary: Author statement of involvement in proteolysis, a very general parent of the specific proteasomal/ERAD catabolism.
    action: KEEP_AS_NON_CORE
    reason: Correct but overly generic; specific SCF-dependent catabolism and ERAD annotations better capture the role.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins
- term:
    id: GO:0036211
    label: protein modification process
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: involved_in
  review:
    summary: Author statement of involvement in protein modification, a very general parent of protein ubiquitination.
    action: KEEP_AS_NON_CORE
    reason: Correct but overly generic; the specific ubiquitination/SCF-catabolism annotations are preferred.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
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: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: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Founding identification of human F-box proteins (including FBXO2); abstract-only in cache. Source of the TAS transferase/proteolysis/modification annotations, which over-attribute catalysis to the receptor subunit.
- id: PMID:21378169
  title: A Competitive binding mechanism between Skp1 and exportin 1 (CRM1) controls the localization of a subset of F-box proteins.
  findings:
  - statement: Skp1 and CRM1/exportin-1 compete for binding to a subset of F-box proteins, controlling their subcellular localization; FBXO2 was assayed and localized to the cytoplasm.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available; primarily about Fbxo7 but FBXO2 cytoplasmic localization (IDA) derives from this study.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding annotation.
- id: PMID:27705803
  title: A High-Density Map for Navigating the Human Polycomb Complexome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Polycomb complexome map; source of a bare protein binding annotation.
- 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 a 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 a bare protein binding annotation.
- id: PMID:34445249
  title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract-only in cache; basis for NAS SCF complex membership and SCF-dependent catabolism annotations.
- id: PMID:34515398
  title: FBXO2/SCF ubiquitin ligase complex directs xenophagy through recognizing bacterial surface glycan.
  findings:
  - statement: FBXO2, a glycoprotein-specific SCF substrate receptor, recognizes GlcNAc side chains of the group A Streptococcus surface carbohydrate and promotes ubiquitin-mediated xenophagy; FBXO2 knockout decreases ubiquitin accumulation and xenophagic degradation of bacteria. FBXO2/FBXO6/FBXO27 are FBA-family lectins that bind high-mannose N-glycoproteins and act as ERAD ubiquitin-ligase subunits.
    reference_section_type: DISCUSSION
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; experimentally establishes FBXO2 glycan-recognition-dependent xenophagy and recapitulates the FBA-family lectin/ERAD role.
- 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 study; source of a bare protein binding annotation.
- 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/FBXO2/FBXO2-deep-research-falcon.md
  title: Falcon deep research report for human FBXO2
  findings:
  - statement: FBXO2/Fbs1 is the substrate-recognition adaptor of an SCF (SKP1-CUL1-RBX1-FBXO2) E3 ligase, not itself an enzyme; the F-box binds SKP1 and the C-terminal domain binds substrate while RBX1-associated E2 executes ubiquitin transfer.
    supporting_text: FBXO2 is best understood as a **substrate-recognition adaptor** that confers specificity to an SCF E3 ligase complex (SKP1–CUL1–RBX1–FBXO2). In this architecture, the **F-box** binds **SKP1**, which bridges to **CUL1/RBX1**, while FBXO2's C-terminal region binds the substrate; ubiquitin transfer is executed by the RBX1-associated E2 enzyme.
  - statement: FBXO2 recognizes a glycan-based degron, binding the innermost N-glycan core (Man3GlcNAc2) through a small hydrophobic pocket, preferring high-mannose N-glycans on denatured/misfolded glycoproteins.
    supporting_text: it binds the **innermost N-glycan core** (described as **Man3GlcNAc2** / innermost GlcNAc2 moiety) using a **small hydrophobic pocket** in its SBD, with preference for **high-mannose N-glycans** and **denatured/misfolded glycoproteins** (where the core glycan becomes accessible).
  - statement: Lectin-type F-box proteins such as FBXO2 act in the nucleocytoplasmic compartment on retrotranslocated ER glycoproteins as part of ERAD.
    supporting_text: lectin-type F-box proteins such as FBXO2 are described as operating in the **nucleocytoplasmic compartment**, where they can recognize **retrotranslocated ER glycoproteins** and promote their ubiquitination as part of **ER-associated degradation (ERAD)** and broader proteostasis mechanisms.
  - statement: Glycoprotein quality-control substrates cited for the Fbs1/Fbs2 pathway include integrin beta-1, TCRalpha, asialoglycoprotein receptor H2a, and CFTR-deltaF508.
    supporting_text: Examples of glycoprotein targets/processes cited in the mechanistic literature include **integrin β1, TCRα, asialoglycoprotein receptor H2a**, and **CFTRΔF508** as glycoproteins in the orbit of Fbs1/Fbs2-mediated quality control.
  - statement: FBXO2 mediates clearance of damaged lysosomes (lysophagy) in CNS contexts; loss delays clearance and exacerbates neurodegeneration in a Niemann-Pick C model.
    supporting_text: Fbxo2 functions as part of an SCF complex and **mediates clearance of damaged lysosomes** in CNS contexts. Loss of Fbxo2 **delayed clearance of damaged lysosomes** and reduced viability after lysosomal damage in mouse primary cortical cultures; in an NPC disease model, Fbxo2 deficiency **exacerbated neurodegeneration and reduced survival**.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Falcon synthesis of peer-reviewed reviews (Yoshida 2019, Yoshida & Tanaka 2018, Suzuki & Fujihira 2021) and primary work (Liu 2020 JCI Insight) corroborates the FBA-lectin/ERAD mechanism, the Man3GlcNAc2 sugar-degron, and named substrates; cross-checked against UniProt. Recent cancer studies (p53, Hsp47) are context-dependent and partly preprints, treated as leads only.
core_functions:
- description: Substrate-recognition subunit of the SCF(FBXO2) E3 ubiquitin ligase that uses its FBA lectin domain to bind N-linked high-mannose oligosaccharides on misfolded/denatured glycoproteins retrotranslocated from the ER, targeting them for ubiquitination and proteasomal degradation via ERAD.
  molecular_function:
    id: GO:0030246
    label: carbohydrate binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/FBXO2/FBXO2-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
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
- description: As the substrate receptor within SCF(FBXO2) (SKP1-CUL1-RBX1-FBXO2), contributes to SCF-dependent proteasomal ubiquitin-dependent catabolism of glycoprotein substrates, bridging glycan-bearing clients to the CUL1-RBX1 catalytic core via SKP1.
  molecular_function:
    id: GO:0030246
    label: carbohydrate binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
    supporting_text: Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
proposed_new_terms: []
suggested_questions:
- question: What is the endogenous high-mannose glycoprotein substrate repertoire of SCF(FBXO2) in different tissues, and how is substrate selection partitioned among the FBA paralogs FBXO2, FBXO6, and FBXO27?
- question: How are FBXO2's neuronal/synaptic roles (dendritic spine, synaptic protein catabolism) and its lysophagy/xenophagy functions mechanistically related to its core ERAD lectin activity, and do they use distinct substrate pools?
suggested_experiments:
- description: Glycan-array and ITC/SPR binding assays with purified FBXO2 FBA domain (wild type vs carbohydrate-binding-site mutants at residues 173, 210-212, 278-279) to quantify high-mannose vs GlcNAc specificity and map the binding determinants.
- description: Quantitative ubiquitinome/proteome profiling in FBXO2-knockout versus wild-type cells (neuronal and epithelial) under ER-stress and ERAD-substrate challenge to define the endogenous glycoprotein substrate set and assess redundancy with FBXO6/FBXO27.