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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
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GO:0031398
positive regulation of protein ubiquitination
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
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.
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.
Supporting Evidence:
PMID:16797541
F-Box proteins (FBPs) are variable adaptor proteins that earmark protein substrates for ubiquination and destruction by the proteasome.
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GO:0005515
protein binding
|
IPI
PMID:16797541 Proteasomal degradation of the multifunctional regulator YB-... |
KEEP AS NON CORE |
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.
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.
Supporting Evidence:
file:human/FBXO33/FBXO33-uniprot.txt
Q7Z6M2; P67809: YBX1; NbExp=6; IntAct=EBI-8555452, EBI-354065;
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GO:0005515
protein binding
|
IPI
PMID:21145461 Dynamics of cullin-RING ubiquitin ligase network revealed by... |
KEEP AS NON CORE |
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.
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.
Supporting Evidence:
file:human/FBXO33/FBXO33-uniprot.txt
Q7Z6M2; Q13616: CUL1; NbExp=2; IntAct=EBI-8555452, EBI-359390;
|
|
GO:0005515
protein binding
|
IPI
PMID:24981860 Human-chromatin-related protein interactions identify a deme... |
KEEP AS NON CORE |
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.
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.
Supporting Evidence:
file:human/FBXO33/FBXO33-uniprot.txt
Interacts via its N-terminus with YBX1 CSD domain.
file:human/FBXO33/FBXO33-deep-research-falcon.md
FBXO33 interacts with YBX1 and is implicated in **ubiquitin-dependent degradation of YBX1**, with downstream relevance to bone marrow stromal cell (BMSC) aging
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GO:0005515
protein binding
|
IPI
PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complex... |
KEEP AS NON CORE |
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.
Reason: Captures a real SCF-component interaction (SKP1) but the bare protein binding term is uninformative; subsumed by the SCF complex annotation.
Supporting Evidence:
file:human/FBXO33/FBXO33-uniprot.txt
Q7Z6M2; P63208: SKP1; NbExp=6; IntAct=EBI-8555452, EBI-307486;
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GO:0005515
protein binding
|
IPI
PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... |
KEEP AS NON CORE |
Summary: IntAct interaction with SKP1 (P63208) from a dual proteome-scale, cell-specific interactome study. Bare protein binding is uninformative.
Reason: High-throughput interactome capturing the SKP1 interaction; bare protein binding is uninformative and not a core function.
Supporting Evidence:
file:human/FBXO33/FBXO33-uniprot.txt
Q7Z6M2; P63208: SKP1; NbExp=6; IntAct=EBI-8555452, EBI-307486;
|
|
GO:0005515
protein binding
|
IPI
PMID:40205054 Multimodal cell maps as a foundation for structural and func... |
KEEP AS NON CORE |
Summary: IntAct interaction with SKP1 (P63208) from a multimodal cell-map structural/functional genomics study. Bare protein binding is uninformative.
Reason: High-throughput interactome capturing the SKP1 interaction; bare protein binding is uninformative and not a core function.
Supporting Evidence:
file:human/FBXO33/FBXO33-uniprot.txt
Q7Z6M2; P63208: SKP1; NbExp=6; IntAct=EBI-8555452, EBI-307486;
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GO:0016567
protein ubiquitination
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IEA
GO_REF:0000041 |
KEEP AS NON CORE |
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.
Reason: Correct but generic; the specific GO:0031146 (SCF-dependent proteasomal ubiquitin-dependent catabolic process) better captures the core biological role.
Supporting Evidence:
file:human/FBXO33/FBXO33-uniprot.txt
PATHWAY: Protein modification; protein ubiquitination.
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GO:0019005
SCF ubiquitin ligase complex
|
NAS
PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... |
ACCEPT |
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.
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.
Supporting Evidence:
file:human/FBXO33/FBXO33-uniprot.txt
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO33) formed of CUL1, SKP1, RBX1 and FBXO33.
|
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GO:0031146
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
|
NAS
PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... |
ACCEPT |
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.
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.
Supporting Evidence:
PMID:16797541
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.
file:human/FBXO33/FBXO33-deep-research-falcon.md
FBXO33's role in a **CUL1-based ubiquitination pathway** contributing to proteostasis by promoting ubiquitination and reducing toxic aggregation/insolubility of expanded polyQ proteins.
|
Q: 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?
Q: 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)?
Q: 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?
Experiment: 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.
Experiment: 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.
Experiment: 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.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The research target is human FBXO33 (synonym FBX33) encoding F-box only protein 33, consistent across the primary literature retrieved here (e.g., papers explicitly naming “F-box only protein 33 (FBXO33)” and studying it in human cell models and/or human tissues). FBXO33 is described as an F-box protein functioning within a Cullin-1 (CUL1)-based Cullin-RING ubiquitin ligase (CRL), i.e., an SCF-like E3 ligase, consistent with the UniProt-provided domain context (F-box and LRR-like features) and with its experimentally demonstrated roles as a substrate-recruiting factor for ubiquitination and proteasomal degradation. (chen2019fipoqfbxo33acullin‐1‐based pages 1-2, chen2019fipoqfbxo33acullin‐1‐based pages 11-13)
F-box proteins are typically the substrate-recognition modules of SCF (SKP1–CUL1–RBX1) E3 ubiquitin ligases, coupling a target protein (“substrate”) to the CUL1-based ubiquitin ligase machinery so the substrate can be polyubiquitinated and, often, degraded by the proteasome. In the polyglutamine disease context, Chen et al. explicitly frame FBXO33 as an F-box substrate receptor acting in a CUL1-based CRL pathway, with functional data supporting recruitment of an expanded polyQ substrate for ubiquitination and clearance. (chen2019fipoqfbxo33acullin‐1‐based pages 1-2, chen2019fipoqfbxo33acullin‐1‐based pages 11-13)
Across the mechanistic studies retrieved, the primary function supported for FBXO33 is:
- E3 ubiquitin ligase substrate adaptor/receptor within a CUL1-based CRL/SCF-like complex, promoting ubiquitination of specific substrates and affecting their stability/aggregation. (chen2019fipoqfbxo33acullin‐1‐based pages 1-2, chen2019fipoqfbxo33acullin‐1‐based pages 11-13)
FBXO33 is therefore not an enzyme catalyzing a small-molecule reaction; its “substrate specificity” is protein-substrate specificity, determined by binding interactions (e.g., defined domains/regions of substrates such as p53 or YBX1). (wu2025lactylationdriventranscriptionalactivation pages 7-10, xiao2023splicingfactorybx1 pages 11-14)
A foundational mechanistic study (Chen et al., 2019; Journal of Neurochemistry, June 2019, DOI: 10.1111/jnc.14669) provides evidence that FBXO33 modulates ubiquitination and aggregation properties of expanded polyglutamine ataxin-3 constructs:
- Selective association with expanded polyQ: FBXO33 co-immunoprecipitates preferentially with aggregate-forming expanded Q78 ataxin-3 construct (EGFP-SCA3tr-Q78) but not with unexpanded Q27. (chen2019fipoqfbxo33acullin‐1‐based pages 11-13)
- Promotes ubiquitination and reduces aggregation: FBXO33 overexpression increases solubility of Q78 and reduces aggregates (filter retardation/aggregate assays), with typical replicate reporting n = 3 for key cell-model assays. (chen2019fipoqfbxo33acullin‐1‐based pages 11-13)
- Proteasome-dependent mechanism: The anti-aggregation effect is blocked by a proteasome inhibitor (lactacystin) but not by chloroquine (lysosome inhibitor), indicating a primary proteasome/UPS dependency. (chen2019fipoqfbxo33acullin‐1‐based pages 9-11)
- Subcellular localization: FBXO33 (with CUL1 in the same experimental context) is reported to localize to both nucleus and cytoplasm. (chen2019fipoqfbxo33acullin‐1‐based pages 11-13)
Interpretation: These data support FBXO33’s role in a CUL1-based ubiquitination pathway contributing to proteostasis by promoting ubiquitination and reducing toxic aggregation/insolubility of expanded polyQ proteins. (chen2019fipoqfbxo33acullin‐1‐based pages 1-2, chen2019fipoqfbxo33acullin‐1‐based pages 11-13)
A recent high-impact study (Xiao et al., 2023; The EMBO Journal, March 2023, DOI: 10.15252/embj.2022111762) provides evidence that FBXO33 interacts with YBX1 and is implicated in ubiquitin-dependent degradation of YBX1, with downstream relevance to bone marrow stromal cell (BMSC) aging:
- Physical interaction + binding-site mapping: Co-immunoprecipitation (co-IP) supports an FBXO33–YBX1 interaction; YBX1 mapping suggests amino acids 42–53 (“pocket”) and 128–322 (C-terminus) are important for FBXO33 binding. (xiao2023splicingfactorybx1 pages 11-14)
- Compound mechanism (sciadopitysin): Sciadopitysin slows YBX1 degradation in cycloheximide chase and decreases YBX1 ubiquitination (MG132-assisted ubiquitination assays), and is reported to reduce FBXO33 protein and suppress the FBXO33–YBX1 co-IP signal, consistent with stabilizing YBX1 by interfering with FBXO33-mediated ubiquitination/degradation. (xiao2023splicingfactorybx1 pages 11-14)
- In vivo quantitative bone outcomes: With sciadopitysin (treatment group n = 8), the study reports improvements in bone parameters including increased BV/TV, Tb.Th, and Tb.N, increased osteoblast-related measures (including MAR and BFR), fewer adipocytes, and no change in osteoclast numbers—consistent with a functional outcome of stabilizing YBX1 in aging bone contexts. (xiao2023splicingfactorybx1 pages 11-14)
Interpretation: This positions FBXO33 as a regulator of a nuclear splicing factor (YBX1) and connects FBXO33 biology to aging-associated stem/stromal cell fate and bone phenotypes, providing a concrete example of a small-molecule intervention acting on a pathway in which FBXO33 is a key node. (xiao2023splicingfactorybx1 pages 11-14, xiao2023splicingfactorybx1 pages 14-15)
A mechanistic cancer study (Wu et al., 2025; Cell Death & Disease, February 2025, DOI: 10.1038/s41419-025-07372-y) reports that FBXO33 binds p53 and regulates p53 stability via ubiquitination in gallbladder cancer:
- Binding and domain mapping: Co-IP indicates FBXO33 binds p53, with interaction mapped to p53 (aa 100–293) and FBXO33 (aa 111–555). (wu2025lactylationdriventranscriptionalactivation pages 7-10)
- Ubiquitination sites: FBXO33 modulates p53 polyubiquitination at K291 and K292. (wu2025lactylationdriventranscriptionalactivation pages 7-10, wu2025lactylationdriventranscriptionalactivation pages 1-2)
- Post-transcriptional control: FBXO33 perturbation changes p53 protein stability without altering p53 mRNA; MG132 reverses FBXO33-dependent p53 reduction and CHX chase supports altered p53 half-life. (wu2025lactylationdriventranscriptionalactivation pages 7-10)
- Wild-type preference: The study reports FBXO33 preferentially increases ubiquitination of wild-type p53 relative to common mutant p53 variants. (wu2025lactylationdriventranscriptionalactivation pages 7-10)
- Clinical sample datapoint: In a small described subset, 11 cases showed FBXO33 higher in cancer than adjacent tissue while p53 was higher in adjacent tissue, consistent with an inverse relationship. (wu2025lactylationdriventranscriptionalactivation pages 7-10)
Interpretation: While outside the requested 2023–2024 window, this provides a detailed mechanistic model of FBXO33 substrate selection (p53) and illustrates that FBXO33 may act as an oncogenic driver in some contexts by destabilizing tumor suppressors. (wu2025lactylationdriventranscriptionalactivation pages 7-10, wu2025lactylationdriventranscriptionalactivation pages 1-2)
Wei et al. (2024; Frontiers in Bioscience, August 2024, DOI: 10.31083/j.fbl2908296) reports that FBXO33 suppresses stemness/metastasis traits in non-small-cell lung cancer (NSCLC) via MYC:
- The paper’s central claim is that FBXO33 promotes ubiquitination and degradation of MYC, reducing stem cell-like properties and metastasis-related behaviors in NSCLC models. (wei2024theubiquitine3 pages 1-1)
Evidence limitation note: In the retrieved text snippet, detailed effect sizes (e.g., hazard ratios, fold-changes, quantitative assay readouts) were not accessible; thus this report treats the MYC mechanism as supported at the level of the paper’s stated results but cannot extract additional numerical statistics from the available excerpt. (wei2024theubiquitine3 pages 1-1)
Fischer et al. (2023; Frontiers in Physiology, March 2023, DOI: 10.3389/fphys.2023.1134339) identifies Fbxo33 (rat ortholog) as a hypertrophy-modulating gene in primary cardiomyocytes:
- siRNA depletion increased cell size in phenylephrine-stimulated neonatal rat cardiomyocytes (reported 1.31 ± 0.04, p < 0.001 vs control). (fischer2023identificationofhypertrophymodulating pages 6-8)
- Protein synthesis increased by 3H-isoleucine incorporation (reported 1.58 ± 0.06, p < 0.001). (fischer2023identificationofhypertrophymodulating pages 6-8)
Interpretation: This is functional-genomics evidence that decreasing Fbxo33 activity can promote hypertrophic growth programs in cardiomyocytes; it does not identify substrates, but supports that FBXO33-associated CRL activity is relevant in cardiac cell-size control. (fischer2023identificationofhypertrophymodulating pages 6-8)
The strongest 2023 advance in this corpus is the FBXO33–YBX1 axis as a concrete mechanistic link between ubiquitin-mediated protein turnover and BMSC fate during aging, alongside an experimental small-molecule (sciadopitysin) that stabilizes YBX1 by interfering with this axis and improving bone microarchitecture metrics. (xiao2023splicingfactorybx1 pages 11-14, xiao2023splicingfactorybx1 pages 14-15)
The 2023 cardiomyocyte screen extends FBXO33 relevance beyond cancer/neurodegeneration to hypertrophic remodeling, with clear quantitative outcomes (effect sizes and p-values) for knockdown phenotypes. (fischer2023identificationofhypertrophymodulating pages 6-8)
The 2024 NSCLC study positions FBXO33 as a potential tumor suppressive E3 substrate adaptor in that disease context by promoting degradation of an oncogenic transcription factor (MYC). (wei2024theubiquitine3 pages 1-1)
A direct “implementation-like” example is the use of sciadopitysin in an in vivo aging/bone context, where the compound stabilizes YBX1 and is associated with improved bone structural parameters (e.g., BV/TV, Tb.Th, Tb.N) with n = 8 in the in vivo group described in the retrieved text. This supports the concept that modulating protein stability through an FBXO33-linked axis can yield measurable physiological outcomes. (xiao2023splicingfactorybx1 pages 11-14)
The cancer literature indicates FBXO33 may be context-dependent—potentially tumor suppressive via MYC degradation in NSCLC (2024) but oncogenic via p53 destabilization in gallbladder cancer (2025). Such context dependence is typical of ubiquitin system substrate adaptors and implies that any biomarker/therapeutic use would require tumor-type and p53/MYC context stratification. (wei2024theubiquitine3 pages 1-1, wu2025lactylationdriventranscriptionalactivation pages 7-10)
Open Targets aggregates human genetic and functional evidence linking FBXO33 (ENSG00000165355) to several traits/diseases including insomnia, smoking initiation, glomerulonephritis, and others, with association scores on the order of ~0.23–0.28 and evidence counts of 5 in the tool output. These associations are useful for hypothesis generation but do not, on their own, specify molecular mechanism. (OpenTargets Search: -FBXO33)
Open Targets URL (target page): https://platform.opentargets.org/target/ENSG00000165355 (OpenTargets Search: -FBXO33)
The following table consolidates the best-supported functional claims and the highest-value sources (including DOIs/URLs and accessible quantitative details).
| Claim/function | Evidence type/model | Key quantitative/statistical detail | Primary source (first author year, journal) | URL/DOI |
|---|---|---|---|---|
| FBXO33 acts as an E3 ligase/substrate receptor that binds wild-type p53 and promotes its polyubiquitination and proteasomal degradation, driving EMT/metastatic traits in gallbladder cancer | Human gallbladder cancer study; co-IP, ubiquitination assays, CHX chase, MG132 rescue, domain mapping, xenografts, clinical specimens | 82 paraffin-embedded tumor specimens analyzed; 11 paired cases showed FBXO33 higher in tumor while p53 was higher in adjacent tissue; p53 half-life was longer after sh-FBXO33 and shorter after Flag-FBXO33; binding mapped to p53 aa100-293 and FBXO33 aa111-555; ubiquitination at p53 K291/K292; knockdown reduced migration/EMT and tumor growth (wu2025lactylationdriventranscriptionalactivation pages 7-10, wu2025lactylationdriventranscriptionalactivation pages 1-2, wu2025lactylationdriventranscriptionalactivation pages 4-7, wu2025lactylationdriventranscriptionalactivation pages 13-14) | Wu 2025, Cell Death & Disease | https://doi.org/10.1038/s41419-025-07372-y |
| FBXO33 suppresses stem cell-like properties and metastasis in NSCLC by promoting ubiquitination and degradation of MYC | Human NSCLC study; title/abstract-level evidence from peer-reviewed primary paper | Paper reports FBXO33 is low in NSCLC and inversely correlated with overall survival; overexpression promoted MYC ubiquitination/degradation and suppressed proliferation, migration, invasion, and stemness, but detailed fold-changes/HRs were not available in retrieved evidence (wei2024theubiquitine3 pages 1-1, wu2025lactylationdriventranscriptionalactivation pages 13-14) | Wei 2024, Frontiers in Bioscience | https://doi.org/10.31083/j.fbl2908296 |
| FBXO33 is a Cul1-based F-box ligase component that modulates ubiquitination, solubility, and aggregation of expanded ATXN3/polyQ proteins | Human SK-N-MC cells plus Drosophila genetic modifier work; co-IP, overexpression, ubiquitination assays, filter retardation, inhibitor studies, localization | FBXO33 overexpression increased SDS-soluble SCA3tr-Q78 and reduced filter-retardation-detected aggregates (n=3); selectively co-immunoprecipitated with expanded Q78 but not Q27; effect was blocked by proteasome inhibitor lactacystin, not chloroquine; Cul1 and FBXO33 localized to both nucleus and cytoplasm; co-expression reduced fraction of cells with polyQ aggregates (chen2019fipoqfbxo33acullin‐1‐based pages 9-11, chen2019fipoqfbxo33acullin‐1‐based pages 7-9, chen2019fipoqfbxo33acullin‐1‐based pages 1-2, chen2019fipoqfbxo33acullin‐1‐based pages 11-13, chen2019fipoqfbxo33acullin‐1‐based pages 4-6) | Chen 2019, Journal of Neurochemistry | https://doi.org/10.1111/jnc.14669 |
| FBXO33 interacts with YBX1 and contributes to YBX1 ubiquitination-dependent degradation; sciadopitysin stabilizes YBX1 partly by disrupting the FBXO33-YBX1 axis | Human/mouse BMSC aging study; co-IP with deletion mapping, CHX chase, ubiquitination assays with MG132, pharmacologic stabilization | YBX1 regions aa42-53 and aa128-322 were required for FBXO33 binding; sciadopitysin slowed YBX1 degradation, decreased YBX1 ubiquitination, lowered FBXO33 protein, and reduced FBXO33-YBX1 co-IP signal; in vivo treatment group n=8 showed increased BV/TV, Tb.Th, Tb.N, osteoblast numbers, MAR, and BFR, with fewer adipocytes and no osteoclast change (xiao2023splicingfactorybx1 pages 11-14, xiao2022orchestrationofalternative pages 11-14, xiao2023splicingfactorybx1 pages 14-15) | Xiao 2023, The EMBO Journal | https://doi.org/10.15252/embj.2022111762 |
| FBXO33 is a negative regulator of cardiomyocyte hypertrophy in a functional screen | siRNA screen in neonatal rat cardiomyocytes with automated microscopy and 3H-isoleucine incorporation | Fbxo33 knockdown increased mean cell size to 1.31 ± 0.04 under PE treatment (p < 0.001) and increased 3H-isoleucine incorporation to 1.58 ± 0.06 (p < 0.001), indicating enhanced hypertrophic growth when Fbxo33 is depleted (fischer2023identificationofhypertrophymodulating pages 6-8) | Fischer 2023, Frontiers in Physiology | https://doi.org/10.3389/fphys.2023.1134339 |
| Human genetics/association resources link FBXO33 to several traits and diseases, but these are association-level signals rather than mechanistic functional proof | Open Targets integrated disease-target evidence | Open Targets reported evidence sizes of 5 for insomnia, smoking initiation, disease of peritoneum, abnormality of the gastrointestinal tract, and glomerulonephritis; association scores included ~0.260 for insomnia, ~0.258 for smoking initiation, ~0.235 for disease of peritoneum/GI abnormality, and ~0.283 for glomerulonephritis (OpenTargets Search: -FBXO33) | Open Targets Platform, accessed via tool context | https://platform.opentargets.org/target/ENSG00000165355 |
Table: This table summarizes the main experimentally supported functions and disease links for human FBXO33, emphasizing direct substrate/interactor evidence, model systems, and quantitative findings. It is useful for distinguishing strong mechanistic evidence from broader association-level annotations.
The most defensible current functional annotation for human FBXO33 (Q7Z6M2) based on the retrieved evidence is that 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. Mechanistically supported interacting substrates include expanded ATXN3/polyQ (proteostasis, nucleus/cytoplasm), YBX1 (ubiquitin-dependent stability; BMSC aging and bone phenotypes), and p53 (wild-type preference; EMT/metastasis phenotypes in gallbladder cancer). A 2024 study further supports a role for FBXO33 in MYC ubiquitination/degradation and suppression of stemness/metastasis in NSCLC, though quantitative details were not extractable from the available excerpt. (chen2019fipoqfbxo33acullin‐1‐based pages 11-13, xiao2023splicingfactorybx1 pages 11-14, wu2025lactylationdriventranscriptionalactivation pages 7-10, wei2024theubiquitine3 pages 1-1)
References
(chen2019fipoqfbxo33acullin‐1‐based pages 1-2): Zhefan Stephen Chen, Azaria Kam Yan Wong, Tat Cheung Cheng, Alex Chun Koon, and Ho Yin Edwin Chan. Fipoq/fbxo33, a cullin‐1‐based ubiquitin ligase complex component modulates ubiquitination and solubility of polyglutamine disease protein. Journal of Neurochemistry, 149:781-798, Jun 2019. URL: https://doi.org/10.1111/jnc.14669, doi:10.1111/jnc.14669. This article has 35 citations and is from a domain leading peer-reviewed journal.
(chen2019fipoqfbxo33acullin‐1‐based pages 11-13): Zhefan Stephen Chen, Azaria Kam Yan Wong, Tat Cheung Cheng, Alex Chun Koon, and Ho Yin Edwin Chan. Fipoq/fbxo33, a cullin‐1‐based ubiquitin ligase complex component modulates ubiquitination and solubility of polyglutamine disease protein. Journal of Neurochemistry, 149:781-798, Jun 2019. URL: https://doi.org/10.1111/jnc.14669, doi:10.1111/jnc.14669. This article has 35 citations and is from a domain leading peer-reviewed journal.
(wu2025lactylationdriventranscriptionalactivation pages 7-10): Zhenheng Wu, You Peng, Wen Chen, Feng Xia, Tieshan Song, and Qiming Ke. Lactylation-driven transcriptional activation of fbxo33 promotes gallbladder cancer metastasis by regulating p53 polyubiquitination. Cell Death & Disease, Feb 2025. URL: https://doi.org/10.1038/s41419-025-07372-y, doi:10.1038/s41419-025-07372-y. This article has 23 citations and is from a peer-reviewed journal.
(xiao2023splicingfactorybx1 pages 11-14): Ye Xiao, Guang-Ping Cai, Xu Feng, Yu-Jue Li, Wan-Hui Guo, Qiaoyue Guo, Yan Huang, Tian Su, Changjun Li, Xianghang Luo, Yongjun Zheng, and Mi Yang. Splicing factor ybx1 regulates bone marrow stromal cell fate during aging. The EMBO Journal, Mar 2023. URL: https://doi.org/10.15252/embj.2022111762, doi:10.15252/embj.2022111762. This article has 77 citations.
(chen2019fipoqfbxo33acullin‐1‐based pages 9-11): Zhefan Stephen Chen, Azaria Kam Yan Wong, Tat Cheung Cheng, Alex Chun Koon, and Ho Yin Edwin Chan. Fipoq/fbxo33, a cullin‐1‐based ubiquitin ligase complex component modulates ubiquitination and solubility of polyglutamine disease protein. Journal of Neurochemistry, 149:781-798, Jun 2019. URL: https://doi.org/10.1111/jnc.14669, doi:10.1111/jnc.14669. This article has 35 citations and is from a domain leading peer-reviewed journal.
(xiao2023splicingfactorybx1 pages 14-15): Ye Xiao, Guang-Ping Cai, Xu Feng, Yu-Jue Li, Wan-Hui Guo, Qiaoyue Guo, Yan Huang, Tian Su, Changjun Li, Xianghang Luo, Yongjun Zheng, and Mi Yang. Splicing factor ybx1 regulates bone marrow stromal cell fate during aging. The EMBO Journal, Mar 2023. URL: https://doi.org/10.15252/embj.2022111762, doi:10.15252/embj.2022111762. This article has 77 citations.
(wu2025lactylationdriventranscriptionalactivation pages 1-2): Zhenheng Wu, You Peng, Wen Chen, Feng Xia, Tieshan Song, and Qiming Ke. Lactylation-driven transcriptional activation of fbxo33 promotes gallbladder cancer metastasis by regulating p53 polyubiquitination. Cell Death & Disease, Feb 2025. URL: https://doi.org/10.1038/s41419-025-07372-y, doi:10.1038/s41419-025-07372-y. This article has 23 citations and is from a peer-reviewed journal.
(wei2024theubiquitine3 pages 1-1): Qiong Wei, Zichun Liu, Jingfeng Zhu, Wenyan Jiang, Haiqin Xie, Ganzhu Feng, and Keming Wang. The ubiquitin e3 ligase fbxo33 suppresses stem cell-like properties and metastasis in non-small-cell lung cancer by promoting ubiquitination and degradation of myc. Frontiers in bioscience, 29 8:296, Aug 2024. URL: https://doi.org/10.31083/j.fbl2908296, doi:10.31083/j.fbl2908296. This article has 7 citations and is from a peer-reviewed journal.
(fischer2023identificationofhypertrophymodulating pages 6-8): Maximillian Fischer, Moritz Jakab, Marc N. Hirt, Tessa R. Werner, Stefan Engelhardt, and Antonio Sarikas. Identification of hypertrophy-modulating cullin-ring ubiquitin ligases in primary cardiomyocytes. Frontiers in Physiology, Mar 2023. URL: https://doi.org/10.3389/fphys.2023.1134339, doi:10.3389/fphys.2023.1134339. This article has 5 citations.
(OpenTargets Search: -FBXO33): Open Targets Query (-FBXO33, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(wu2025lactylationdriventranscriptionalactivation pages 13-14): Zhenheng Wu, You Peng, Wen Chen, Feng Xia, Tieshan Song, and Qiming Ke. Lactylation-driven transcriptional activation of fbxo33 promotes gallbladder cancer metastasis by regulating p53 polyubiquitination. Cell Death & Disease, Feb 2025. URL: https://doi.org/10.1038/s41419-025-07372-y, doi:10.1038/s41419-025-07372-y. This article has 23 citations and is from a peer-reviewed journal.
(wu2025lactylationdriventranscriptionalactivation pages 4-7): Zhenheng Wu, You Peng, Wen Chen, Feng Xia, Tieshan Song, and Qiming Ke. Lactylation-driven transcriptional activation of fbxo33 promotes gallbladder cancer metastasis by regulating p53 polyubiquitination. Cell Death & Disease, Feb 2025. URL: https://doi.org/10.1038/s41419-025-07372-y, doi:10.1038/s41419-025-07372-y. This article has 23 citations and is from a peer-reviewed journal.
(chen2019fipoqfbxo33acullin‐1‐based pages 7-9): Zhefan Stephen Chen, Azaria Kam Yan Wong, Tat Cheung Cheng, Alex Chun Koon, and Ho Yin Edwin Chan. Fipoq/fbxo33, a cullin‐1‐based ubiquitin ligase complex component modulates ubiquitination and solubility of polyglutamine disease protein. Journal of Neurochemistry, 149:781-798, Jun 2019. URL: https://doi.org/10.1111/jnc.14669, doi:10.1111/jnc.14669. This article has 35 citations and is from a domain leading peer-reviewed journal.
(chen2019fipoqfbxo33acullin‐1‐based pages 4-6): Zhefan Stephen Chen, Azaria Kam Yan Wong, Tat Cheung Cheng, Alex Chun Koon, and Ho Yin Edwin Chan. Fipoq/fbxo33, a cullin‐1‐based ubiquitin ligase complex component modulates ubiquitination and solubility of polyglutamine disease protein. Journal of Neurochemistry, 149:781-798, Jun 2019. URL: https://doi.org/10.1111/jnc.14669, doi:10.1111/jnc.14669. This article has 35 citations and is from a domain leading peer-reviewed journal.
(xiao2022orchestrationofalternative pages 11-14): Ye Xiao, Guang-Ping Cai, Xu Feng, Qi Guo, Yan Huang, Tian Su, Chang-Jun Li, Xiang-Hang Luo, Yong-Jun Zheng, and Mi Yang. Orchestration of alternative splicing regulates bone marrow mesenchymal stem cells fate during aging. BioRxiv, May 2022. URL: https://doi.org/10.1101/2022.05.27.493685, doi:10.1101/2022.05.27.493685. This article has 0 citations.
UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|LRR (aux domain IPR032675) ; PN-node mapping: group=mapped GO:1990756; subtype/type/branch=no_mapping; class=context_only (GO:0061630).This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.
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.