id: Q9Y3I1
gene_symbol: FBXO7
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXO7 (also called FBX7; PARK15) is the substrate-recognition (F-box)
  component of an SCF (SKP1-CUL1-RBX1-F-box) E3 ubiquitin-protein ligase complex,
  SCF(FBXO7). As an F-box protein it acts as a ligase-substrate adaptor: it
  recruits substrates and bridges them, via its F-box domain binding to SKP1, to
  the catalytic cullin-RING core (RBX1), and is not itself the catalytic
  ubiquitin transferase. The protein has a modular architecture comprising an
  N-terminal ubiquitin-like (Ubl) region that mediates binding to the E3 ligase
  PRKN/Parkin, a CDK6-interaction region, an FP (Fbxo7/PI31) dimerization domain
  that mediates homodimerization and interaction with the proteasome inhibitor
  PSMF1/PI31, the F-box domain, and a C-terminal proline-rich region that serves
  as a substrate-binding module. SCF(FBXO7) ubiquitination is not exclusively
  degradative: it can build K48-linked chains that target substrates for
  proteasomal degradation or K63-linked chains with non-proteolytic
  signaling/assembly outcomes, depending on substrate and context. Documented
  SCF(FBXO7) substrates include the
  cell-cycle regulator DLGAP5/HURP, the inhibitor-of-apoptosis protein
  BIRC2/cIAP1, TRAF2 and the NF-kappa-B cofactor UXT isoform 2 (whose degradation
  inhibits NF-kappa-B signaling), the NAD+-dependent deacetylase SIRT7 (K48-
  linked polyubiquitination promoting H2O2-induced cell death), the kinase
  GSK3-beta and the mitochondrial import receptor TOMM20 (modified in part with
  non-degradative chains), and, in tumor-suppressor contexts, the
  mitochondrial-fission factor INF2 and the arginine methyltransferase PRMT1
  (K48-linked polyubiquitination coupling FBXO7 to control of mitochondrial
  division and serine biosynthesis, respectively). Beyond canonical
  SCF activity, FBXO7 has SCF-independent roles: it relocates from the cytosol to
  depolarized mitochondria downstream of PINK1 and promotes PRKN/Parkin
  recruitment and mitofusin ubiquitination to drive selective autophagy of
  damaged mitochondria (mitophagy); it associates with the proteasome and
  regulates proteasome assembly/activity through PSMF1/PI31; and it activates
  cyclin D/CDK6 complexes to promote cell-cycle progression, with proto-oncogenic
  transforming activity. FBXO7 protein stability is itself controlled by the
  deubiquitinase USP7. FBXO7 is predominantly
  cytoplasmic/cytosolic with a minor nuclear pool. Recessive loss-of-function and
  missense mutations (e.g. T22M, R378G, R498X) cause early-onset autosomal
  recessive parkinsonian-pyramidal syndrome (Parkinson disease 15, PARK15).
alternative_products:
- name: '1'
  id: Q9Y3I1-1
- name: '2'
  id: Q9Y3I1-2
  sequence_note: VSP_041073, VSP_041074
- name: '3'
  id: Q9Y3I1-3
  sequence_note: VSP_044723
existing_annotations:
- term:
    id: GO:1903599
    label: positive regulation of autophagy of mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of a positive role in mitophagy, consistent with the experimentally demonstrated FBXO7 function downstream of PINK1 in Parkin-mediated mitophagy.
    action: ACCEPT
    reason: Core biological process; the IBA inference agrees with direct IMP/IDA evidence (PMID:23933751, PMID:26310625) that FBXO7 promotes clearance of depolarized mitochondria.
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: Here we show that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and acts in Parkin-mediated mitophagy.
    - reference_id: file:human/FBXO7/FBXO7-deep-research-falcon.md
      supporting_text: FBXO7 participates in mitochondrial quality control by interacting with **PINK1 and Parkin** and facilitating Parkin recruitment to damaged mitochondria in PARK15 biology.
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic assignment of protein kinase binding, reflecting the documented FBXO7 interactions with the kinases CDK6 and PINK1.
    action: KEEP_AS_NON_CORE
    reason: Real and mechanistically meaningful (CDK6 activation of cyclin D complexes; PINK1 in the mitophagy pathway) but a subsidiary binding activity rather than the core adaptor function.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Interacts with CDK6 and promotes its interaction with D-type cyclin.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of nuclear localization; FBXO7 has a documented minor nuclear pool in addition to its predominant cytoplasmic localization.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization is real but minor; the predominant and functionally dominant compartment is the cytoplasm/cytosol.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: A minor proportion is detected in the nucleus (PubMed:16096642).
- 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; the predominant compartment of FBXO7.
    action: ACCEPT
    reason: Correct predominant localization, supported experimentally (PMID:16096642, PMID:18495667).
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Note=Predominantly cytoplasmic (PubMed:16096642).
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of mitochondrial localization, consistent with the experimentally observed relocation of FBXO7 from the cytosol to depolarized mitochondria.
    action: ACCEPT
    reason: Correct conditional localization; FBXO7 relocates to depolarized mitochondria during mitophagy (PMID:23933751).
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Relocates from the cytosol to depolarized mitochondria (PubMed:23933751).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of cytosolic localization from the UniProt subcellular location; the predominant compartment of FBXO7.
    action: ACCEPT
    reason: Correct core localization, supported experimentally (PMID:23933751).
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic assignment of protein kinase binding, reflecting documented CDK6 and PINK1 interactions.
    action: KEEP_AS_NON_CORE
    reason: Real binding activity (CDK6, PINK1) but subsidiary to the core ligase-substrate adaptor function.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Interacts with CDK6 and promotes its interaction with D-type cyclin.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16278047
  qualifier: enables
  review:
    summary: Interaction captured during characterization of a related brain-expressed F-box protein (FBX25). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction but the bare protein binding term is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22632967
  qualifier: enables
  review:
    summary: Interaction captured in a cyclin F (FBXO1)/RRM2 study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23933751
  qualifier: enables
  review:
    summary: Interaction with PRKN/Parkin (and PINK1) from the mitophagy study; a functionally important interaction, but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the meaningful FBXO7-PRKN/PINK1 interaction, but bare protein binding is uninformative; the functional relationship is captured by the mitophagy process annotations.
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: the Ubl domain of Fbxo7 directly mediates Parkin interaction
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: High-throughput proteome-scale interactome mapping. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  qualifier: enables
  review:
    summary: High-throughput interactome perturbation 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: High-throughput quantitative 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27705803
  qualifier: enables
  review:
    summary: High-throughput Polycomb complexome interaction 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput interactome (protein communities/disease networks). 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: High-throughput variant-interactome disruption 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: High-throughput neurodegenerative-disease 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: High-throughput dual proteome-scale 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: High-throughput multimodal cell-map 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:1901526
    label: positive regulation of mitophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment of positive regulation of mitophagy, consistent with the experimentally established FBXO7 mitophagy role.
    action: ACCEPT
    reason: Core biological process; agrees with direct experimental evidence (PMID:23933751, PMID:26310625).
    supported_by:
    - reference_id: PMID:26310625
      supporting_text: The WT FBXO7 protein is vital to cell mitophagy and can facilitate mitophagy to protect cells, whereas mutant FBXO7 inhibits mitophagy.
- 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 catabolic process FBXO7 enables.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific GO:0031146 (SCF-dependent catabolic process) and K48-linked ubiquitination annotations better capture the role.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence assignment of nucleoplasm localization, consistent with the documented minor nuclear pool of FBXO7.
    action: KEEP_AS_NON_CORE
    reason: Real but minor nuclear localization; the predominant compartment is the cytoplasm/cytosol.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: A minor proportion is detected in the nucleus (PubMed:16096642).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence assignment of cytosolic localization, the predominant FBXO7 compartment.
    action: ACCEPT
    reason: Correct core localization; supported by direct experimental fractionation (PMID:23933751).
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:16096642
  qualifier: located_in
  review:
    summary: Experimental localization showing FBXO7 in the nucleus (minor pool) in addition to predominant cytoplasm.
    action: KEEP_AS_NON_CORE
    reason: Real minor nuclear localization documented in this study; predominant compartment is cytoplasmic.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: A minor proportion is detected in the nucleus (PubMed:16096642).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:16096642
  qualifier: located_in
  review:
    summary: Experimental localization showing FBXO7 is predominantly cytoplasmic. Core compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Note=Predominantly cytoplasmic (PubMed:16096642).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:18495667
  qualifier: located_in
  review:
    summary: Experimental localization to the cytoplasm consistent with the predominant FBXO7 compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:16096642, ECO:0000269|PubMed:18495667}.
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    summary: Author statement that FBXO7 is an F-box component of an SCF E3 ubiquitin ligase complex. Core complex membership.
    action: ACCEPT
    reason: Core localization/complex; FBXO7 is the substrate-receptor F-box subunit of SCF(FBXO7) (CUL1, SKP1, RBX1, FBXO7).
    supported_by:
    - reference_id: PMID:34445249
      supporting_text: 'The SKP1, CUL1, F-box protein (SCF) complex encompasses a group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation.'
- 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 statement linking the SCF complex (including F-box proteins) to SCF-dependent proteasomal degradation. Core biological process.
    action: ACCEPT
    reason: Core biological process; FBXO7 targets substrates for SCF-dependent proteasomal degradation.
    supported_by:
    - reference_id: PMID:34445249
      supporting_text: 'These SCF complexes are distinguishable by variable F-box proteins, which determine substrate specificity.'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:33010352
  qualifier: is_active_in
  review:
    summary: Direct evidence that FBXO7 acts in the nucleus, where it colocalizes with and ubiquitinates its substrate UXT-V2.
    action: KEEP_AS_NON_CORE
    reason: Documents a functionally relevant nuclear pool (UXT-V2 degradation) but nuclear localization is minor relative to the predominant cytoplasm/cytosol.
    supported_by:
    - reference_id: PMID:33010352
      supporting_text: We find that UXT-V2 colocalizes with Fbxo7 in the cell nucleus.
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:33010352
  qualifier: involved_in
  review:
    summary: Direct evidence that SCF(FBXO7) mediates SCF-dependent proteasomal degradation of UXT-V2. Core biological process.
    action: ACCEPT
    reason: Core biological process with direct experimental support; SCF(FBXO7) polyubiquitinates UXT-V2 for proteasomal degradation.
    supported_by:
    - reference_id: PMID:33010352
      supporting_text: 'Together, our study reveals that SCF(Fbxo7) mediates the proteasomal degradation of UXT-V2 causing the inhibition of the NF-κB signaling pathway.'
- term:
    id: GO:0043124
    label: negative regulation of canonical NF-kappaB signal transduction
  evidence_type: IDA
  original_reference_id: PMID:33010352
  qualifier: involved_in
  review:
    summary: Direct evidence that SCF(FBXO7)-mediated degradation of UXT-V2 inhibits NF-kappa-B signaling. Well-supported biological process.
    action: ACCEPT
    reason: Directly demonstrated; FBXO7 negatively regulates NF-kappa-B signaling via UXT-V2 (and TRAF2/cIAP1) ubiquitination.
    supported_by:
    - reference_id: PMID:33010352
      supporting_text: 'Together, our study reveals that SCF(Fbxo7) mediates the proteasomal degradation of UXT-V2 causing the inhibition of the NF-κB signaling pathway.'
- term:
    id: GO:0070936
    label: protein K48-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:33010352
  qualifier: involved_in
  review:
    summary: Direct evidence that SCF(FBXO7) builds K48 (and K63) polyubiquitin chains on UXT-V2.
    action: ACCEPT
    reason: Directly demonstrated K48-linked ubiquitination of a substrate, the canonical degradative topology used by SCF(FBXO7).
    supported_by:
    - reference_id: PMID:33010352
      supporting_text: This substrate is polyubiquitinated by SCF(Fbxo7) with K48 and K63 ubiquitin chain linkages in vitro and in vivo.
- term:
    id: GO:1901526
    label: positive regulation of mitophagy
  evidence_type: IDA
  original_reference_id: PMID:26310625
  qualifier: involved_in
  review:
    summary: Direct evidence that WT FBXO7 facilitates mitophagy whereas PD-linked mutants inhibit it. Core biological process.
    action: ACCEPT
    reason: Core biological process with direct experimental support.
    supported_by:
    - reference_id: PMID:26310625
      supporting_text: The WT FBXO7 protein is vital to cell mitophagy and can facilitate mitophagy to protect cells, whereas mutant FBXO7 inhibits mitophagy.
- term:
    id: GO:1903377
    label: negative regulation of oxidative stress-induced neuron intrinsic apoptotic
      signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:25029497
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence linking an FBXO7 variant (Y52C) to altered TRAF2 turnover and neuronal outgrowth in a PD-protective context.
    action: KEEP_AS_NON_CORE
    reason: A context-specific neuronal stress/apoptosis-modulating role inferred from variant phenotypes, not the core SCF adaptor function.
    supported_by:
    - reference_id: PMID:25029497
      supporting_text: After induced differentiation, SH-SY5Y cells expressing Cys52 FBXO7 displayed increased neuronal outgrowth.
- term:
    id: GO:1903377
    label: negative regulation of oxidative stress-induced neuron intrinsic apoptotic
      signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:26310625
  qualifier: acts_upstream_of
  review:
    summary: Evidence that FBXO7 acts as a stress-response protein with cytoprotective (and, when mutant/aggregated, neurotoxic) effects under oxidative stress.
    action: KEEP_AS_NON_CORE
    reason: A context-specific neuronal stress-response role; mechanistically downstream of the core mitophagy/proteostasis functions rather than a distinct core process.
    supported_by:
    - reference_id: PMID:26310625
      supporting_text: Here we demonstrated that wild-type (WT) FBXO7 is a stress response protein and it can play both cytoprotective and neurotoxic roles.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:36646384
  qualifier: is_active_in
  review:
    summary: Direct evidence that FBXO7 colocalizes with its substrate SIRT7 mainly in the nucleus, where it acts to degrade SIRT7.
    action: KEEP_AS_NON_CORE
    reason: Documents a functionally relevant nuclear pool (SIRT7 degradation) but nuclear localization is minor relative to the predominant cytoplasm/cytosol.
    supported_by:
    - reference_id: PMID:36646384
      supporting_text: immunohistochemical analysis of SH-SY5Y cells revealed that endogenous FBXO7 and SIRT7 colocalized mainly in the nucleus
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:36646384
  qualifier: involved_in
  review:
    summary: Direct evidence that FBXO7 drives SCF-dependent proteasomal degradation of SIRT7. Core biological process.
    action: ACCEPT
    reason: Core biological process; FBXO7 promotes proteasomal degradation of SIRT7 (the more specific GO:0031146 SCF-dependent process is also annotated).
    supported_by:
    - reference_id: PMID:36646384
      supporting_text: we identified FBXO7 as a novel E3 ligase for SIRT7 that negatively regulates intracellular SIRT7 levels through SCF-dependent Lys-48-linked polyubiquitination and proteasomal degradation
- term:
    id: GO:0070936
    label: protein K48-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:36646384
  qualifier: involved_in
  review:
    summary: Direct evidence that FBXO7 promotes K48-linked polyubiquitination of SIRT7.
    action: ACCEPT
    reason: Directly demonstrated K48-linked ubiquitination of a substrate (SIRT7), the canonical degradative topology of SCF(FBXO7).
    supported_by:
    - reference_id: PMID:36646384
      supporting_text: These results demonstrated that FBXO7 directly mediates the polyubiquitination of SIRT7 by targeting K48-linked polyubiquitin chains.
- term:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:36646384
  qualifier: enables
  review:
    summary: Direct evidence that FBXO7 acts as an SCF substrate-recognition adaptor recruiting SIRT7 for ubiquitination. Core molecular function.
    action: ACCEPT
    reason: Core molecular function; FBXO7 is the substrate-recognition adaptor of SCF(FBXO7), bridging substrates to the catalytic cullin-RING core.
    supported_by:
    - reference_id: PMID:36646384
      supporting_text: FBXO7 is an adaptor protein in the SKP1-Cullin-1-F-box (SCF) E3 ligase complex that facilitates the ubiquitination of substrates.
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:15145941
  qualifier: part_of
  review:
    summary: Direct evidence that FBXO7 functions within an SCF(FBXO7) complex (with SKP1 and CUL1) to ubiquitinate HURP/DLGAP5. Core complex membership.
    action: ACCEPT
    reason: Core localization/complex; FBXO7 is a functional F-box subunit of an SCF ubiquitin-ligase complex.
    supported_by:
    - reference_id: PMID:15145941
      supporting_text: 'In the SCF(Fbx7) complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner.'
- term:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:15145941
  qualifier: enables
  review:
    summary: Direct evidence that FBXO7 functions as a substrate-recruiting adaptor of the SCF complex, binding HURP via its proline-rich region. Core molecular function.
    action: ACCEPT
    reason: Core molecular function; FBXO7 is a functional SCF adaptor with the proline-rich region serving as the substrate-binding module.
    supported_by:
    - reference_id: PMID:15145941
      supporting_text: Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21378169
  qualifier: enables
  review:
    summary: Interaction captured in a study of SKP1/CRM1 competition controlling F-box protein localization. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction relevant to FBXO7 nuclear/cytoplasmic shuttling (SKP1, CRM1) but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO7) formed of CUL1, SKP1, RBX1 and FBXO7.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:26310625
  qualifier: located_in
  review:
    summary: Direct evidence that FBXO7 concentrates into mitochondria upon stress, forming aggregates. Conditional/stress-induced localization.
    action: ACCEPT
    reason: Correct conditional localization; FBXO7 relocates to mitochondria under stress/depolarization, consistent with its mitophagy role.
    supported_by:
    - reference_id: PMID:26310625
      supporting_text: 'Upon stress, the endogenous WT FBXO7 gets up-regulated, concentrates into mitochondria and forms FBXO7 aggregates in mitochondria.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25029497
  qualifier: enables
  review:
    summary: Interaction with TRAF2 captured in the FBXO7 Y52C polymorphism study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally meaningful FBXO7-TRAF2 interaction but bare protein binding is uninformative; the substrate relationship is captured by the ubiquitination/NF-kappa-B annotations.
    supported_by:
    - reference_id: PMID:25029497
      supporting_text: 'Moreover, Cys52 FBXO7 showed stronger interaction with TRAF2 and promoted TRAF2 ubiquitination'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:16510124
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 nuclear localization (colocalized with cIAP1/BIRC2 in cytoplasm and nucleus). Minor nuclear pool.
    action: KEEP_AS_NON_CORE
    reason: Real but minor nuclear localization; predominant compartment is cytoplasm/cytosol.
    supported_by:
    - reference_id: PMID:16510124
      supporting_text: 'When co-expressed in cells, cIAP1 and Fbxo7 co-localized remarkably both in the cytoplasm and nucleus'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:25029497
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 nuclear localization, consistent with the documented minor nuclear pool.
    action: KEEP_AS_NON_CORE
    reason: Real but minor nuclear localization; predominant compartment is cytoplasm/cytosol.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: A minor proportion is detected in the nucleus (PubMed:16096642).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:16510124
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 cytoplasmic localization (colocalized with cIAP1/BIRC2). Core compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support.
    supported_by:
    - reference_id: PMID:16510124
      supporting_text: 'When co-expressed in cells, cIAP1 and Fbxo7 co-localized remarkably both in the cytoplasm and nucleus'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:25029497
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 cytoplasmic localization. Core compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Note=Predominantly cytoplasmic (PubMed:16096642).
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:25029497
  qualifier: involved_in
  review:
    summary: Direct evidence that FBXO7 promotes ubiquitination and turnover of TRAF2. A parent of the more specific SCF-dependent catabolic process.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic relative to the specific GO:0031146 (SCF-dependent proteasomal catabolic process); here the substrate is TRAF2.
    supported_by:
    - reference_id: PMID:25029497
      supporting_text: 'In cells expressing Cys52 FBXO7, the level of TNF receptor-associated factor 2 (TRAF2) was significantly reduced.'
- term:
    id: GO:0010975
    label: regulation of neuron projection development
  evidence_type: IMP
  original_reference_id: PMID:25029497
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that an FBXO7 variant alters neuronal outgrowth in differentiated SH-SY5Y cells.
    action: KEEP_AS_NON_CORE
    reason: A context-specific neuronal phenotype linked to an FBXO7 variant, not the core SCF adaptor function.
    supported_by:
    - reference_id: PMID:25029497
      supporting_text: After induced differentiation, SH-SY5Y cells expressing Cys52 FBXO7 displayed increased neuronal outgrowth.
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:16510124
  qualifier: involved_in
  review:
    summary: Direct evidence that FBXO7 overexpression promotes ubiquitination of cIAP1/BIRC2. Generic parent process.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific SCF-dependent catabolic process (GO:0031146) better captures the role. The cIAP1/BIRC2 substrate relationship is meaningful.
    supported_by:
    - reference_id: PMID:16510124
      supporting_text: 'Furthermore, we showed that overexpression of Fbxo7 promotes the ubiquitination of cIAP1.'
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IPI
  original_reference_id: PMID:18495667
  qualifier: enables
  review:
    summary: Interaction with the kinase CDK6 (and PSMF1) documented in the FP-domain structural study.
    action: KEEP_AS_NON_CORE
    reason: Real CDK6 binding (FBXO7 activates cyclin D-CDK6) but subsidiary to the core adaptor function.
    supported_by:
    - reference_id: PMID:18495667
      supporting_text: 'SCF(Fbxo7) is known to catalyze the ubiquitination of hepatoma-up-regulated protein (HURP) and the inhibitor of apoptosis (IAP) protein but also functions as an activator of cyclin D-Cdk6 complexes.'
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:16510124
  qualifier: enables
  review:
    summary: Interaction with the ubiquitin ligase cIAP1/BIRC2 (itself a RING E3) documented as an FBXO7 substrate interaction.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction with a ubiquitin ligase substrate (BIRC2) but is subsidiary to the core adaptor function.
    supported_by:
    - reference_id: PMID:16510124
      supporting_text: 'we performed a yeast two-hybrid screen and identified an F-box protein Fbxo7 as a cIAP1 interacting protein.'
- term:
    id: GO:0043130
    label: ubiquitin binding
  evidence_type: IDA
  original_reference_id: PMID:25029497
  qualifier: enables
  review:
    summary: Assignment of ubiquitin binding to FBXO7. A plausible but ancillary activity relative to the core substrate-adaptor function.
    action: KEEP_AS_NON_CORE
    reason: If accurate, ubiquitin binding is a subsidiary molecular feature; the core function is the ligase-substrate adaptor activity. Not central to the documented FBXO7 roles.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: 'The ubiquitin-like region mediates interaction with PRKN.'
- term:
    id: GO:0046982
    label: protein heterodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:18495667
  qualifier: enables
  review:
    summary: Direct evidence that FBXO7 heterodimerizes with PSMF1/PI31 via the shared FP domain (and homodimerizes).
    action: KEEP_AS_NON_CORE
    reason: Real FP-domain-mediated dimerization with PSMF1/PI31 (relevant to proteasome regulation) but a structural/binding property rather than the core adaptor function.
    supported_by:
    - reference_id: PMID:18495667
      supporting_text: We identify PI31 as an Fbxo7.Skp1 binding partner and show that this interaction requires an N-terminal domain present in both proteins that we term the FP (Fbxo7/PI31) domain.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:21347293
  qualifier: located_in
  review:
    summary: Direct evidence that wild-type FBXO7 isoform 1 displays mostly diffuse nuclear localization, with loss of nuclear localization in PARK15 mutants.
    action: KEEP_AS_NON_CORE
    reason: This study emphasizes a nuclear pool, but UniProt and other studies establish that FBXO7 is predominantly cytoplasmic; nuclear localization is treated as non-core.
    supported_by:
    - reference_id: PMID:21347293
      supporting_text: 'the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:21347293
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 cytoplasmic localization, including mutant-induced cytoplasmic mislocalization. Core compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support; PARK15 N-terminal mutations shift FBXO7 to the cytoplasm.
    supported_by:
    - reference_id: PMID:21347293
      supporting_text: 'N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:23656991
  qualifier: located_in
  review:
    summary: Immunohistochemical detection of FBXO7 in human brain neurons; widespread expression. Reported nuclear/cytoplasmic neuronal staining.
    action: KEEP_AS_NON_CORE
    reason: Brain immunoreactivity localization; nuclear pool is minor relative to predominant cytoplasm.
    supported_by:
    - reference_id: PMID:23656991
      supporting_text: 'We detected widespread brain FBXO7 immunoreactivity, with the highest levels in neurons of the cerebral cortex, putamen, and cerebellum.'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:23656991
  qualifier: located_in
  review:
    summary: Immunohistochemical detection of FBXO7 in the cytoplasm of human brain neurons. Consistent with predominant cytoplasmic localization.
    action: ACCEPT
    reason: Consistent with the core cytoplasmic localization of FBXO7 in neurons.
    supported_by:
    - reference_id: PMID:23656991
      supporting_text: 'We detected widespread brain FBXO7 immunoreactivity, with the highest levels in neurons of the cerebral cortex, putamen, and cerebellum.'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: TAS
  original_reference_id: PMID:16510124
  qualifier: part_of
  review:
    summary: Author statement that F-box proteins such as FBXO7 are specificity-determining subunits of SCF ubiquitin ligases. Core complex membership.
    action: ACCEPT
    reason: Core localization/complex; FBXO7 is the F-box substrate-receptor subunit of an SCF E3 ligase.
    supported_by:
    - reference_id: PMID:16510124
      supporting_text: 'Since F-box proteins are specificity determining subunits of SCF ubiquitin protein ligases, our results suggest that Fbxo7 can mediate the ubiquitination of cIAP1 by SCF ubiquitin protein ligase'
- term:
    id: GO:0097409
    label: glial cytoplasmic inclusion
  evidence_type: IDA
  original_reference_id: PMID:23656991
  qualifier: located_in
  review:
    summary: Direct immunoreactivity for FBXO7 within alpha-synuclein-positive glial cytoplasmic inclusions in multiple system atrophy. A disease-pathology localization.
    action: KEEP_AS_NON_CORE
    reason: Real IDA immunoreactivity in pathological inclusions, but this is a disease-associated localization, not a core physiological compartment.
    supported_by:
    - reference_id: PMID:23656991
      supporting_text: 'FBXO7 immunoreactivity was detected in large proportions of α-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions)'
- term:
    id: GO:0097414
    label: classical Lewy body
  evidence_type: IDA
  original_reference_id: PMID:23656991
  qualifier: located_in
  review:
    summary: Direct immunoreactivity for FBXO7 within alpha-synuclein-positive Lewy bodies in Parkinson disease. A disease-pathology localization.
    action: KEEP_AS_NON_CORE
    reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment.
    supported_by:
    - reference_id: PMID:23656991
      supporting_text: 'FBXO7 immunoreactivity was detected in large proportions of α-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions)'
- term:
    id: GO:0097462
    label: Lewy neurite
  evidence_type: IDA
  original_reference_id: PMID:23656991
  qualifier: located_in
  review:
    summary: Direct immunoreactivity for FBXO7 within alpha-synuclein-positive Lewy neurites. A disease-pathology localization.
    action: KEEP_AS_NON_CORE
    reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment.
    supported_by:
    - reference_id: PMID:23656991
      supporting_text: 'FBXO7 immunoreactivity was detected in large proportions of α-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions)'
- term:
    id: GO:1990037
    label: Lewy body core
  evidence_type: IDA
  original_reference_id: PMID:23656991
  qualifier: located_in
  review:
    summary: Direct immunoreactivity for FBXO7 colocalizing with alpha-synuclein in Lewy body structures. A disease-pathology localization.
    action: KEEP_AS_NON_CORE
    reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment.
    supported_by:
    - reference_id: PMID:23656991
      supporting_text: 'where it colocalized with α-synuclein in PD and MSA cases'
- term:
    id: GO:1990038
    label: Lewy body corona
  evidence_type: IDA
  original_reference_id: PMID:23656991
  qualifier: located_in
  review:
    summary: Direct immunoreactivity for FBXO7 colocalizing with alpha-synuclein in Lewy body structures. A disease-pathology localization.
    action: KEEP_AS_NON_CORE
    reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment.
    supported_by:
    - reference_id: PMID:23656991
      supporting_text: 'where it colocalized with α-synuclein in PD and MSA cases'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:21378169
  qualifier: located_in
  review:
    summary: Direct evidence relating to FBXO7 nuclear/cytoplasmic distribution governed by SKP1/CRM1 competition.
    action: KEEP_AS_NON_CORE
    reason: Real but minor nuclear localization governed by SKP1/CRM1 shuttling; predominant compartment is cytoplasm.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: A minor proportion is detected in the nucleus (PubMed:16096642).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:21378169
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 cytoplasmic localization controlled by SKP1/CRM1 competition. Core compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Note=Predominantly cytoplasmic (PubMed:16096642).
- term:
    id: GO:0040012
    label: regulation of locomotion
  evidence_type: IDA
  original_reference_id: PMID:26310625
  qualifier: involved_in
  review:
    summary: Organismal locomotor phenotype associated with FBXO7 (Drosophila dopamine-neuron degeneration and PD-related models), reflecting its mitophagy/neuroprotection role.
    action: KEEP_AS_NON_CORE
    reason: An organismal/neurodegeneration phenotype downstream of the core mitophagy function rather than a distinct cell-autonomous core process.
    supported_by:
    - reference_id: PMID:26310625
      supporting_text: 'The overexpression of WT FBXO7 could lead to FBXO7 protein aggregation and dopamine neuron degeneration in transgenic Drosophila heads.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome neddylation/CRL-machinery pathway annotation placing FBXO7 in the cytosol. The cytosol is the predominant FBXO7 compartment.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment for the SCF(FBXO7) complex.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome CRL-machinery pathway annotation placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome CRL-machinery pathway annotation (CAND1 binding) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome CRL-machinery pathway annotation (COMMD/CAND1) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome CRL-machinery pathway annotation (COP9 signalosome deneddylation) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome CRL-machinery pathway annotation (DCUN1D3) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome ubiquitination-pathway annotation (Ub transfer from E2 to substrate) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome ubiquitination-pathway annotation (release of E3 from polyubiquitinated substrate) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome ubiquitination-pathway annotation (polyubiquitination of substrate) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome ubiquitination-pathway annotation (interaction of E3 with substrate and E2-Ub complex) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:18495667
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 nuclear localization documented in the FP-domain study. Minor nuclear pool.
    action: KEEP_AS_NON_CORE
    reason: Real but minor nuclear localization; predominant compartment is cytoplasm/cytosol.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: 'Nucleus {ECO:0000269|PubMed:16096642, ECO:0000269|PubMed:18495667, ECO:0000269|PubMed:33010352}.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:18495667
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 cytosolic localization. Core compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:16096642, ECO:0000269|PubMed:18495667}.
- term:
    id: GO:0000151
    label: ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:23933751
  qualifier: part_of
  review:
    summary: Direct evidence that FBXO7 is part of a ubiquitin ligase complex (the SCF(FBXO7) complex). Generic parent of the specific SCF complex term.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the more specific GO:0019005 (SCF ubiquitin ligase complex) better captures FBXO7's complex membership.
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: 'F-box domain-containing proteins target substrates to SCF-type (Skp1-Cul1-F-box) E3-ubiquitin ligase complexes'
- term:
    id: GO:0000422
    label: autophagy of mitochondrion
  evidence_type: IMP
  original_reference_id: PMID:23933751
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that reducing FBXO7 impairs CCCP-induced mitophagy and that FBXO7 acts in Parkin-mediated mitophagy. Core biological process.
    action: ACCEPT
    reason: Core biological process with direct experimental (IMP) support; FBXO7 knockdown reduces mitophagy and FBXO7 rescues parkin mutant phenotypes.
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: Cells with reduced Fbxo7 expression showed deficiencies in translocation of Parkin to mitochondria, ubiquitination of mitofusin 1 and mitophagy.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:23933751
  qualifier: located_in
  review:
    summary: Direct evidence that FBXO7 relocates from the cytosol to depolarized mitochondria following CCCP treatment. Conditional localization.
    action: ACCEPT
    reason: Correct conditional/stress-induced localization central to the mitophagy function.
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: endogenous Fbxo7 levels were found to decrease steadily in the cytosolic fraction and increase concurrently in the mitochondrial fractions
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:23933751
  qualifier: located_in
  review:
    summary: Direct evidence that FBXO7 is predominantly cytosolic (before relocating to depolarized mitochondria). Core compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support (cell fractionation).
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: 'although both proteins localise predominantly to the cytosol'
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IMP
  original_reference_id: PMID:23933751
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that FBXO7 is required for CCCP-induced mitofusin 1 ubiquitination (via promoting Parkin recruitment). Generic parent process.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; FBXO7 facilitates substrate (Mfn1) ubiquitination chiefly by promoting Parkin recruitment. The specific mitophagy annotations better capture the role.
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: Cells with reduced Fbxo7 expression showed deficiencies in translocation of Parkin to mitochondria, ubiquitination of mitofusin 1 and mitophagy.
- term:
    id: GO:0070585
    label: protein localization to mitochondrion
  evidence_type: IMP
  original_reference_id: PMID:23933751
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that FBXO7 is required for Parkin translocation to depolarized mitochondria. Well-supported process.
    action: ACCEPT
    reason: Directly demonstrated; FBXO7 facilitates Parkin recruitment to mitochondria, a key step in mitophagy.
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: Overall, these data indicate that Fbxo7 facilitates Parkin translocation to the mitochondria in response to depolarisation.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  qualifier: part_of
  review:
    summary: LIFEdb fusion-protein localization assignment of generic protein-containing complex membership.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific SCF ubiquitin ligase complex (GO:0019005) is far more informative.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO7) formed of CUL1, SKP1, RBX1 and FBXO7.
- term:
    id: GO:0031647
    label: regulation of protein stability
  evidence_type: IDA
  original_reference_id: PMID:15145941
  qualifier: involved_in
  review:
    summary: Direct evidence that FBXO7 controls the stability/abundance of its substrate HURP via ubiquitination.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; FBXO7 regulates substrate stability through the more specific SCF-dependent catabolic process (GO:0031146).
    supported_by:
    - reference_id: PMID:15145941
      supporting_text: Depletion of Fbx7 by small interfering RNA leads to depression of HURP ubiquitination and accumulation of HURP abundance.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15145941
  qualifier: enables
  review:
    summary: Interaction with the substrate DLGAP5/HURP (and CUL1/SKP1) from the HURP proteolysis study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the meaningful FBXO7-HURP/DLGAP5 substrate interaction, but bare protein binding is uninformative; captured by the SCF/adaptor annotations.
    supported_by:
    - reference_id: PMID:15145941
      supporting_text: 'In the SCF(Fbx7) complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner.'
- term:
    id: GO:0000151
    label: ubiquitin ligase complex
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: part_of
  review:
    summary: Author statement that F-box proteins are subunits of SCF ubiquitin protein ligases. Generic parent of the SCF complex term.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the more specific GO:0019005 (SCF ubiquitin ligase complex) better captures FBXO7's membership.
    supported_by:
    - reference_id: PMID:10531035
      supporting_text: 'In fact, F-box proteins are one of the four subunits of ubiquitin protein ligases called SCFs.'
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: enables
  review:
    summary: Family-level author statement assigning ubiquitin-protein transferase activity to F-box-containing SCF ligases. FBXO7 is the substrate-recognition adaptor, not the catalytic transferase (the catalytic RING is RBX1).
    action: MODIFY
    reason: FBXO7 itself is not the ubiquitin transferase; it is the substrate-recognition adaptor of the SCF complex. The catalytic transfer is performed by the E2 recruited by the RBX1 RING. The informative molecular function is the ligase-substrate adaptor activity.
    proposed_replacement_terms:
    - id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    supported_by:
    - reference_id: PMID:36646384
      supporting_text: FBXO7 is an adaptor protein in the SKP1-Cullin-1-F-box (SCF) E3 ligase complex that facilitates the ubiquitination of substrates.
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: involved_in
  review:
    summary: Family-level author statement that F-box/SCF proteins drive controlled degradation of cellular regulatory proteins. Generic parent of the specific SCF-dependent process.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific GO:0031146 (SCF-dependent proteasomal catabolic process) better captures FBXO7's role.
    supported_by:
    - reference_id: PMID:10531035
      supporting_text: 'Some F-box proteins have been shown to be critical for the controlled degradation of cellular regulatory proteins'
references:
- 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: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: GO_REF:0000054
  title: Gene Ontology annotation based on curation of intracellular localizations
    of expressed fusion proteins in living cells
  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: 'PubMed-verified; foundational family-level description establishing F-box proteins as the substrate-recognition subunits of SCF ubiquitin ligases. Source of the TAS transferase/catabolic/complex annotations; the bare transferase activity is an over-assignment for the adaptor FBXO7.'
- id: PMID:15145941
  title: Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-phosphorylated
    hepatoma up-regulated protein (HURP) proteolysis by a proline-rich region.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (abstract-only in cache). Establishes FBXO7 as a functional SCF adaptor using its proline-rich region to recruit the substrate HURP/DLGAP5; source of the core adaptor activity and SCF complex annotations.'
- id: PMID:16096642
  title: Transforming activity of Fbxo7 is mediated specifically through regulation
    of cyclin D/cdk6.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (full text available). Establishes the cyclin D/CDK6 activation and proto-oncogenic transforming activity of FBXO7 and its predominantly cytoplasmic localization with a minor nuclear pool.'
- id: PMID:16278047
  title: Characterization of FBX25, encoding a novel brain-expressed F-box protein.
  findings: []
- id: PMID:16510124
  title: The F-box protein Fbxo7 interacts with human inhibitor of apoptosis protein
    cIAP1 and promotes cIAP1 ubiquitination.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (abstract-only in cache). Establishes the FBXO7-cIAP1/BIRC2 interaction and FBXO7-promoted cIAP1 ubiquitination; source of SCF complex, cytoplasm/nucleus and ubiquitination annotations.'
- id: PMID:18495667
  title: Structure of a conserved dimerization domain within the F-box protein Fbxo7
    and the PI31 proteasome inhibitor.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (abstract-only in cache). Defines the FP (Fbxo7/PI31) domain mediating FBXO7 homodimerization and heterodimerization with PSMF1/PI31; source of heterodimerization and CDK6-binding annotations.'
- id: PMID:21347293
  title: Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal
    syndrome (PARK15).
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: 'PubMed-verified (full text available). Reports FBXO7 isoform expression and nuclear localization of isoform 1, with PARK15 mutations causing cytoplasmic mislocalization. Emphasizes a nuclear pool that other studies treat as minor relative to predominant cytoplasm.'
- 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: []
- id: PMID:22632967
  title: Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome
    integrity and DNA repair.
  findings: []
- id: PMID:23656991
  title: FBXO7 immunoreactivity in α-synuclein-containing inclusions in Parkinson
    disease and multiple system atrophy.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: 'PubMed-verified (abstract-only in cache). Documents FBXO7 immunoreactivity in alpha-synuclein-positive Lewy bodies, Lewy neurites and glial cytoplasmic inclusions; source of disease-pathology localization annotations (kept as non-core).'
- id: PMID:23933751
  title: The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate
    mitophagy.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (full text available). Key paper establishing the SCF-independent mitophagy role: FBXO7 interacts with PINK1/Parkin, relocates to depolarized mitochondria, and promotes Parkin recruitment and Mfn1 ubiquitination; PD mutations disrupt this.'
- id: PMID:25029497
  title: FBXO7 Y52C polymorphism as a potential protective factor in Parkinson's disease.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: 'PubMed-verified (full text available). Y52C polymorphism stabilizes FBXO7, enhances TRAF2 interaction/ubiquitination and increases neuronal outgrowth; source of TRAF2 interaction, catabolic-process and neuron-projection annotations.'
- 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:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding annotation.
- id: PMID:26310625
  title: F-box protein 7 mutations promote protein aggregation in mitochondria and
    inhibit mitophagy.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (abstract-only in cache). Establishes FBXO7 as a stress-response protein essential for mitophagy whose PD mutations promote mitochondrial aggregation and inhibit mitophagy; source of mitophagy, mitochondrion and locomotion annotations.'
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries
    and abundances.
  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: High-throughput interactome; source of a 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 a bare protein binding annotation.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding annotation.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding annotation.
- id: PMID:33010352
  title: The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degradation of UXT
    isoform 2 (UXT-V2) to inhibit the NF-κB signaling pathway.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (full text available). Establishes SCF(FBXO7)-mediated K48/K63 polyubiquitination and proteasomal degradation of UXT-V2, inhibiting NF-kappa-B signaling; source of NF-kappa-B, K48 ubiquitination, SCF-dependent catabolism and nuclear-activity annotations.'
- 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: High-throughput 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: 'PubMed-verified (abstract-only in cache). Review of SCF complex roles in genome/chromosome stability; supports SCF complex membership and SCF-dependent proteasomal catabolism (NAS) annotations. FBXO7-specific chromosome-stability data are in PMID:34791250.'
- id: PMID:36646384
  title: E3 ligase adaptor FBXO7 contributes to ubiquitination and proteasomal degradation
    of SIRT7 and promotes cell death in response to hydrogen peroxide.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (full text available). Establishes FBXO7 as an SCF substrate-recognition adaptor that drives K48-linked polyubiquitination and proteasomal degradation of SIRT7; explicitly describes FBXO7 as an adaptor (not the catalytic transferase). Source of the core adaptor-activity annotation.'
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome/cell map; 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/FBXO7/FBXO7-deep-research-falcon.md
  title: Falcon deep research report for human FBXO7
  findings:
  - statement: FBXO7 is the substrate-recognition adaptor of an SCF-type E3 ubiquitin ligase, whose F-box domain binds SKP1 to link substrates to the CUL1-RBX1 catalytic core.
    supporting_text: FBXO7 is best understood as a **substrate-specifying adaptor** of an **SCF-type E3 ubiquitin ligase**, where its **F-box domain binds SKP1**, linking FBXO7 to the **CUL1–RBX1** catalytic core that recruits an E2~ubiquitin and transfers ubiquitin to substrates.
  - statement: FBXO7-driven ubiquitination is not exclusively degradative; it can generate K48-linked (proteasome-targeting) or K63-linked (non-proteolytic) chains depending on substrate and context.
    supporting_text: A key conceptual point is that **FBXO7-driven ubiquitination is not exclusively degradative**. It can generate **K48-linked polyubiquitin** (often proteasome-targeting) or **K63-linked chains** (often non-proteolytic signaling/trafficking/autophagy-related roles), depending on the substrate and context.
  - statement: Loss of Fbxo7 in mice reduces proteasome activity and produces a parkinsonism-like phenotype, supporting a role in neuronal proteostasis through proteasome assembly/composition tuning.
    supporting_text: 'In mouse models, **loss of Fbxo7** leads to **reduced proteasome activity** and a **parkinsonism-like phenotype**, supporting a role for FBXO7 in neuronal proteostasis.'
  - statement: FBXO7 acts as a context-dependent tumor suppressor, catalyzing predominantly K48-linked polyubiquitination of INF2 (endometrial carcinoma, mitochondrial division control) and of PRMT1 (hepatocellular carcinoma, serine synthesis control).
    supporting_text: Together, these studies support FBXO7 as a context-dependent tumor suppressor via **mitochondrial homeostasis** and **amino-acid metabolism**, consistent with an E3 adaptor that tunes proteostasis, mitochondria, and stress responses.
  - statement: USP7 deubiquitinates and stabilizes FBXO7 by removing K48-linked ubiquitin chains, connecting deubiquitinase control of FBXO7 to cell survival under ER stress.
    supporting_text: USP7 deubiquitinates FBXO7 by removing **K48-linked ubiquitin chains**, preventing FBXO7 proteasomal degradation.
core_functions:
- description: Substrate-recognition (F-box) adaptor of the SCF(FBXO7) E3 ubiquitin
    ligase complex (CUL1-SKP1-RBX1-FBXO7) that recruits substrates (e.g. DLGAP5/HURP,
    BIRC2/cIAP1, TRAF2, UXT-V2, SIRT7) via its proline-rich region and Ubl/FP regions
    and bridges them to the catalytic cullin-RING core for K48-linked polyubiquitination
    and proteasomal degradation.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:36646384
    supporting_text: FBXO7 is an adaptor protein in the SKP1-Cullin-1-F-box (SCF) E3 ligase complex that facilitates the ubiquitination of substrates.
  - reference_id: PMID:15145941
    supporting_text: Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module.
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
- description: SCF-independent regulator of mitophagy that relocates from the cytosol
    to depolarized mitochondria downstream of PINK1, interacts with PINK1 and PRKN/Parkin
    via its N-terminal Ubl region, and promotes Parkin recruitment to mitochondria
    and mitofusin ubiquitination to drive selective autophagic clearance of damaged
    mitochondria.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  locations:
  - id: GO:0005739
    label: mitochondrion
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:23933751
    supporting_text: Here we show that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and acts in Parkin-mediated mitophagy.
  directly_involved_in:
  - id: GO:1901526
    label: positive regulation of mitophagy
- description: Negative regulator of canonical NF-kappa-B signaling, achieved by SCF(FBXO7)-mediated
    K48/K63 polyubiquitination and proteasomal degradation of the NF-kappa-B cofactor
    UXT isoform 2 (and ubiquitination of TRAF2 and cIAP1/BIRC2).
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:33010352
    supporting_text: 'Together, our study reveals that SCF(Fbxo7) mediates the proteasomal degradation of UXT-V2 causing the inhibition of the NF-κB signaling pathway.'
  directly_involved_in:
  - id: GO:0043124
    label: negative regulation of canonical NF-kappaB signal transduction
- description: Proteasome-associated regulator of proteostasis that, through FP-domain
    heterodimerization with the proteasome inhibitor PSMF1/PI31 and ubiquitin signaling
    on proteasomal components, tunes 26S proteasome assembly/activity; loss of FBXO7
    reduces proteasome activity and models a parkinsonism-like phenotype, indicating
    a role in neuronal proteostasis.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:18495667
    supporting_text: We identify PI31 as an Fbxo7.Skp1 binding partner and show that this interaction requires an N-terminal domain present in both proteins that we term the FP (Fbxo7/PI31) domain.
  - reference_id: file:human/FBXO7/FBXO7-deep-research-falcon.md
    supporting_text: 'In mouse models, **loss of Fbxo7** leads to **reduced proteasome activity** and a **parkinsonism-like phenotype**, supporting a role for FBXO7 in neuronal proteostasis.'
proposed_new_terms: []
suggested_questions:
- question: To what extent are FBXO7's SCF-dependent substrate-degradation roles (HURP, cIAP1, TRAF2, UXT-V2, SIRT7) and its SCF-independent roles (PINK1/Parkin mitophagy, PSMF1/PI31 proteasome regulation, cyclin D/CDK6 activation) separable, and which are most relevant to PARK15 neurodegeneration?
- question: How do the FP domain-mediated FBXO7 homodimerization and FBXO7-PSMF1/PI31 heterodimerization regulate proteasome assembly/activity in neurons, and is this disrupted by PARK15 mutations?
- question: Does FBXO7 directly target PRKN/PINK1 for ubiquitination, or does it act mainly as a non-catalytic scaffold promoting Parkin recruitment to depolarized mitochondria?
suggested_experiments:
- description: Reconstitute SCF(FBXO7) in vitro with purified CUL1, SKP1, RBX1, an E2, and candidate substrates (HURP/DLGAP5, SIRT7, UXT-V2) to confirm that FBXO7 functions as a substrate-presenting adaptor (not the catalytic transferase) and to map substrate lysines and chain linkages.
- description: Perform quantitative ubiquitinome and proteome profiling in FBXO7-knockout versus wild-type neuronal cells under basal and mitochondrial-depolarization (CCCP) conditions to define the endogenous SCF(FBXO7) substrate repertoire and its contribution to mitophagy.
- description: Use live-cell imaging with PARK15 patient-derived neurons (T22M, R378G, R498X) to quantify FBXO7 relocation to depolarized mitochondria and Parkin recruitment kinetics, dissecting how each mutation impairs mitophagy.