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 |
|---|---|---|---|
| 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. |
| 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; |
| 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 |
| 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; |
| 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; |
| GO:0016567 protein ubiquitination | 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. |
| 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. |
| 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. |
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Download this section (compressed HTML)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.
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