id: Q7Z6M2
gene_symbol: FBXO33
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXO33 (F-box only protein 33, FBX33) is the substrate-recognition subunit of
  a SCF (SKP1-CUL1-F-box protein) / CRL1-type E3 ubiquitin-protein ligase
  complex. As an F-box "other" (FBXO) protein it lacks the C-terminal leucine-rich
  repeat or WD40 substrate-binding domains found in typical F-box proteins; instead
  it uses its N-terminal region to engage substrate, while its F-box motif (residues
  65-111) docks the adaptor SKP1, which in turn links it to the CUL1 scaffold and
  the catalytic RING subunit RBX1. Within this complex FBXO33 acts as the
  substrate receptor that selects target proteins for poly-ubiquitination and
  subsequent proteasomal degradation; it is the F-box adaptor and not the
  catalytic RING core, and it has been observed in both the nucleus and the
  cytoplasm. The best-documented substrate is the multifunctional cold-shock-domain
  transcription/translation/splicing regulator YBX1 (Y-box binding protein 1,
  YB-1/dbpB/p50): FBXO33 associates with the YBX1 cold-shock domain through its
  N-terminus and targets YBX1 for ubiquitin-dependent proteasomal degradation,
  a function with relevance to bone-marrow stromal cell fate during aging.
  Additional substrate-like targets and context-dependent roles have been
  reported: FBXO33 promotes ubiquitination and clearance of expanded-polyglutamine
  ataxin-3 (ATXN3), reducing toxic aggregation in models of polyglutamine disease
  (a proteostasis/protein-quality-control role); it can promote ubiquitination and
  degradation of MYC (suppressing stemness/metastasis in non-small-cell lung
  cancer) and of wild-type p53 (promoting metastasis in gallbladder cancer),
  illustrating that as a substrate adaptor it can be tumor-suppressive or
  oncogenic depending on the dominant substrate in a given context. FBXO33 was
  originally identified as a gene induced during programmed cell death and has
  also been implicated as a negative modulator of cardiomyocyte hypertrophy. It is
  widely expressed (with enhanced expression in bone) and has been recovered in
  SCF-network and chromatin/Polycomb-related interaction studies.
existing_annotations:
- term:
    id: GO:0031398
    label: positive regulation of protein ubiquitination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (PAN-GO) assignment that FBXO33 promotes protein ubiquitination, consistent with its role as the substrate-recognition subunit that delivers targets to the SCF ubiquitination machinery.
    action: KEEP_AS_NON_CORE
    reason: Biologically consistent (the F-box adaptor enables ubiquitination of its substrates), but this regulatory parent term is less informative than the core SCF complex and SCF-dependent catabolic process annotations. Retained as supportive but non-core.
    supported_by:
    - reference_id: PMID:16797541
      supporting_text: F-Box proteins (FBPs) are variable adaptor proteins that earmark protein substrates for ubiquination and destruction by the proteasome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16797541
  qualifier: enables
  review:
    summary: IntAct-curated interactions from the YB-1 degradation study, capturing FBXO33 binding to SKP1, CUL1 and its substrate YBX1. Bare protein binding is uninformative per curation guidelines, but these are functionally meaningful SCF-component and substrate interactions.
    action: KEEP_AS_NON_CORE
    reason: Records real, functionally important interactions (SKP1, CUL1, YBX1) but the bare GO:0005515 term conveys no specific function; the underlying relationships are captured by the SCF complex, SCF-dependent catabolic process, and substrate-adaptor annotations.
    supported_by:
    - reference_id: file:human/FBXO33/FBXO33-uniprot.txt
      supporting_text: 'Q7Z6M2; P67809: YBX1; NbExp=6; IntAct=EBI-8555452, EBI-354065;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21145461
  qualifier: enables
  review:
    summary: IntAct interaction with CUL1 from a systematic quantitative proteomics study of the cullin-RING ligase network, consistent with FBXO33 assembling into a CUL1-based SCF complex. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Captures a real SCF-component interaction (CUL1) but the bare protein binding term is uninformative; the relationship is better represented by the SCF complex annotation.
    supported_by:
    - reference_id: file:human/FBXO33/FBXO33-uniprot.txt
      supporting_text: 'Q7Z6M2; Q13616: CUL1; NbExp=2; IntAct=EBI-8555452, EBI-359390;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24981860
  qualifier: enables
  review:
    summary: IntAct interaction with the substrate YBX1 (P67809) captured in a chromatin-related protein interaction study. Bare protein binding is uninformative, but the partner is FBXO33's documented degradation substrate.
    action: KEEP_AS_NON_CORE
    reason: Records the real FBXO33-YBX1 interaction but the bare term is uninformative; the substrate relationship is captured by the SCF-dependent catabolic process annotation and the core-function adaptor activity. Falcon-sourced literature (Xiao et al. 2023, EMBO J) independently confirms the FBXO33-YBX1 interaction with binding-site mapping and ties FBXO33-mediated YBX1 ubiquitination/degradation to bone-marrow stromal cell fate during aging.
    supported_by:
    - reference_id: file:human/FBXO33/FBXO33-uniprot.txt
      supporting_text: Interacts via its N-terminus with YBX1 CSD domain.
    - reference_id: file:human/FBXO33/FBXO33-deep-research-falcon.md
      supporting_text: FBXO33 interacts with YBX1 and is implicated in **ubiquitin-dependent degradation of YBX1**, with downstream relevance to bone marrow stromal cell (BMSC) aging
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27705803
  qualifier: enables
  review:
    summary: IntAct interaction with SKP1 (P63208) from a high-density Polycomb complexome map, consistent with F-box docking to the SKP1 adaptor. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Captures a real SCF-component interaction (SKP1) but the bare protein binding term is uninformative; subsumed by the SCF complex annotation.
    supported_by:
    - reference_id: file:human/FBXO33/FBXO33-uniprot.txt
      supporting_text: 'Q7Z6M2; P63208: SKP1; NbExp=6; IntAct=EBI-8555452, EBI-307486;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: IntAct interaction with SKP1 (P63208) from a dual proteome-scale, cell-specific interactome study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome capturing the SKP1 interaction; bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/FBXO33/FBXO33-uniprot.txt
      supporting_text: 'Q7Z6M2; P63208: SKP1; NbExp=6; IntAct=EBI-8555452, EBI-307486;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: IntAct interaction with SKP1 (P63208) from a multimodal cell-map structural/functional genomics study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome capturing the SKP1 interaction; bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/FBXO33/FBXO33-uniprot.txt
      supporting_text: 'Q7Z6M2; P63208: SKP1; NbExp=6; IntAct=EBI-8555452, EBI-307486;'
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-derived electronic assignment of the generic protein ubiquitination process. FBXO33 participates in ubiquitination as the SCF substrate receptor, though it is not the catalytic enzyme.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific GO:0031146 (SCF-dependent proteasomal ubiquitin-dependent catabolic process) better captures the core biological role.
    supported_by:
    - reference_id: file:human/FBXO33/FBXO33-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    summary: ComplexPortal-curated assignment that FBXO33 is part of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex (SCF(FBXO33), CPX-7973). This is the core localization/complex membership of the protein.
    action: ACCEPT
    reason: Core complex membership; FBXO33 is the F-box substrate-recognition subunit of SCF(FBXO33), formed of CUL1, SKP1, RBX1 and FBXO33, as documented in UniProt and ComplexPortal.
    supported_by:
    - reference_id: file:human/FBXO33/FBXO33-uniprot.txt
      supporting_text: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO33) formed of CUL1, SKP1, RBX1 and FBXO33.
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: involved_in
  review:
    summary: ComplexPortal-curated assignment that FBXO33 functions in SCF-dependent proteasomal degradation. This is the core biological process, directly supported by the YBX1 degradation study.
    action: ACCEPT
    reason: Core biological process; FBXO33 is the substrate receptor of an SCF/CUL1-based complex that targets substrates for poly-ubiquitination and proteasomal destruction. This is directly supported for YBX1 (PMID:16797541) and corroborated by Falcon-sourced primary literature documenting FBXO33-driven ubiquitination/clearance of additional substrate-like targets (expanded-polyQ ATXN3, MYC, p53), consistent with the functional placement of FBXO33 as an F-box/SCF (CRL1) substrate-recognition receptor.
    supported_by:
    - reference_id: PMID:16797541
      supporting_text: we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome.
    - reference_id: file:human/FBXO33/FBXO33-deep-research-falcon.md
      supporting_text: FBXO33's role in a **CUL1-based ubiquitination pathway** contributing to proteostasis by promoting ubiquitination and reducing toxic aggregation/insolubility of expanded polyQ 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: PMID:16797541
  title: Proteasomal degradation of the multifunctional regulator YB-1 is mediated by an F-Box protein induced during programmed cell death.
  findings:
  - statement: FBX33/FBXO33, the mouse homolog of human F-box protein 33, is a component of an SCF E3 ubiquitin ligase that targets the multifunctional regulator YB-1 (YBX1)/dbpB/p50 for polyubiquitination and proteasomal degradation; unlike typical F-box proteins it lacks C-terminal LRR/WD40 domains and associates with YB-1 via its N-terminus.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (FEBS Lett 2006, DOI 10.1016/j.febslet.2006.06.023); abstract-only in cache (full_text_available false). Directly establishes FBXO33 as the SCF substrate receptor for YBX1 and the N-terminal substrate-binding mode; foundational for the core-function and YBX1-substrate calls.
- id: PMID:21145461
  title: Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Systematic CRL-network proteomics; source of the IntAct FBXO33-CUL1 interaction, consistent with SCF/CRL1 assembly.
- id: PMID:24981860
  title: Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Chromatin-related interactome; source of the IntAct FBXO33-YBX1 interaction (YBX1 is FBXO33's documented degradation substrate).
- 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 Polycomb complexome map; source of a bare protein binding annotation (SKP1).
- 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 proteome-scale interactome; source of a bare protein binding annotation (SKP1).
- 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 genomics study; source of a bare protein binding annotation (SKP1).
- id: PMID:34445249
  title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  findings:
  - statement: The SCF (SKP1-CUL1-F-box) complex encompasses ~69 E3 ubiquitin ligase complexes distinguished by variable F-box proteins that determine substrate specificity and primarily modify substrates with poly-ubiquitin chains to target them for proteasomal degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Int J Mol Sci 2021, PMC8395177); review of the SCF complex family. Used by ComplexPortal as the NAS reference for the SCF complex and SCF-dependent catabolic process annotations; supports the general SCF framework rather than FBXO33-specific data.
- id: file:human/FBXO33/FBXO33-deep-research-falcon.md
  title: Falcon deep research report for human FBXO33
  findings:
  - statement: FBXO33 is an F-box substrate adaptor of a CUL1-based CRL/SCF-like ubiquitin ligase that selects specific protein substrates for ubiquitination and proteasomal degradation, with documented substrates including YBX1, expanded-polyQ ATXN3, p53 and MYC.
    supporting_text: it is an **F-box substrate adaptor of a CUL1-based CRL/SCF-like ubiquitin ligase**, functioning primarily to **select specific protein substrates (or substrate-like targets)** for ubiquitination and downstream consequences including proteasomal degradation or altered solubility/aggregation.
  - statement: FBXO33 modulates ubiquitination and solubility of expanded-polyglutamine ataxin-3, reducing toxic aggregation in a proteasome-dependent manner, supporting a protein-quality-control/proteostasis role; it localizes to both nucleus and cytoplasm.
    supporting_text: FBXO33's role in a **CUL1-based ubiquitination pathway** contributing to proteostasis by promoting ubiquitination and reducing toxic aggregation/insolubility of expanded polyQ proteins.
  - statement: FBXO33 interacts with YBX1 and contributes to its ubiquitin-dependent degradation, an axis relevant to bone-marrow stromal cell fate during aging.
    supporting_text: FBXO33 interacts with YBX1 and is implicated in **ubiquitin-dependent degradation of YBX1**, with downstream relevance to bone marrow stromal cell (BMSC) aging
  - statement: As a substrate adaptor FBXO33 can be tumor-suppressive (MYC degradation in NSCLC) or oncogenic (p53 destabilization in gallbladder cancer) depending on the dominant substrate context.
    supporting_text: FBXO33 may be context-dependent—potentially **tumor suppressive** via MYC degradation in NSCLC (2024) but **oncogenic** via p53 destabilization in gallbladder cancer (2025).
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: >-
      Falcon synthesis anchored on real primary studies: Chen et al. 2019
      (J Neurochem, doi:10.1111/jnc.14669; ATXN3/polyQ, nucleus+cytoplasm), Xiao
      et al. 2023 (EMBO J, doi:10.15252/embj.2022111762; YBX1/BMSC aging), Wei et
      al. 2024 (Front Biosci, doi:10.31083/j.fbl2908296; MYC/NSCLC), Wu et al. 2025
      (Cell Death Dis, doi:10.1038/s41419-025-07372-y; p53/gallbladder cancer), and
      Fischer et al. 2023 (Front Physiol, doi:10.3389/fphys.2023.1134339;
      cardiomyocyte hypertrophy). These corroborate and substantially extend the
      YBX1-centric annotation already supported by PMID:16797541; Falcon cites
      author-year/DOIs not PMIDs and the papers are not in the local cache, so the
      additional substrates are treated as strong leads (UNVERIFIED) pending
      curator confirmation.
core_functions:
- description: Substrate-recognition (F-box) subunit of an SCF/CRL1 E3 ubiquitin ligase complex (SCF(FBXO33), with SKP1, CUL1 and the RING subunit RBX1) that selects target proteins, notably the cold-shock-domain regulator YBX1/YB-1 bound via the FBXO33 N-terminus, for poly-ubiquitination and proteasomal degradation. FBXO33 is the substrate adaptor, not the catalytic RING.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  in_complex:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  supported_by:
  - reference_id: PMID:16797541
    supporting_text: we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome.
  - reference_id: file:human/FBXO33/FBXO33-uniprot.txt
    supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
proposed_new_terms: []
suggested_questions:
- question: Beyond YBX1, ATXN3/polyQ, MYC and p53, what is the full endogenous substrate repertoire of SCF(FBXO33), and what determines substrate selection given that FBXO33 lacks canonical LRR/WD40 substrate-binding domains and engages substrates via its N-terminal/non-F-box region rather than a classical phosphodegron?
- question: What governs the apparently opposing tumor-suppressive (MYC) versus oncogenic (p53) outcomes of FBXO33 activity in different tissues, and is this driven by tissue-specific substrate availability, FBXO33 expression level, or post-translational regulation (e.g. lactylation-driven transcription reported in gallbladder cancer)?
- question: Does FBXO33-mediated reduction of polyglutamine aggregation operate primarily through proteasomal degradation of expanded ATXN3, and could enhancing FBXO33 activity be protective in polyglutamine diseases?
suggested_experiments:
- description: Reconstitute SCF(FBXO33) in vitro with purified SKP1, CUL1, RBX1, an E2 and ubiquitin, and assay FBXO33-dependent poly-ubiquitination of recombinant YBX1, p53, MYC and expanded-polyQ ATXN3 (with substrate domain/site variants) to confirm direct substrate-adaptor activity and define the determinants of substrate selection.
- description: Perform quantitative ubiquitinome/proteome profiling in FBXO33-knockout versus wild-type cells across tissue contexts (e.g. bone-marrow stromal, lung, gallbladder, neuronal polyQ models), with and without proteasome inhibition, to define the endogenous SCF(FBXO33) substrate set and validate stabilization of YBX1/MYC/p53/ATXN3 upon FBXO33 loss.
- description: Test whether FBXO33 nucleocytoplasmic distribution and the lactylation-driven transcriptional regulation reported in cancer determine which substrates are engaged, by perturbing FBXO33 localization and expression and measuring substrate-specific stability changes.